EP1587505B1 - Wund- und hautpflegezusammensetzungen - Google Patents

Wund- und hautpflegezusammensetzungen Download PDF

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Publication number
EP1587505B1
EP1587505B1 EP03799944A EP03799944A EP1587505B1 EP 1587505 B1 EP1587505 B1 EP 1587505B1 EP 03799944 A EP03799944 A EP 03799944A EP 03799944 A EP03799944 A EP 03799944A EP 1587505 B1 EP1587505 B1 EP 1587505B1
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Prior art keywords
compound
composition
acid
skin
effective amount
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English (en)
French (fr)
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EP1587505A2 (de
EP1587505A4 (de
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Sohail Malik
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Kimberly Clark Worldwide Inc
Kimberly Clark Corp
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Kimberly Clark Worldwide Inc
Kimberly Clark Corp
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Priority claimed from US10/320,730 external-priority patent/US7098189B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • the present invention relates generally to the field of wound healing and to the rejuvenation, renewal, repair and maintenance of healthy skin.
  • Skin is subject to insults by many extrinsic and intrinsic factors.
  • Extrinsic factors that can adversely affect the skin include wounds, ultraviolet radiation (e.g., from sun exposure), environmental pollution, wind, heat, low humidity, harsh surfactants, abrasives, and the like.
  • Intrinsic factors that lead to skin problems include chronological aging and other biochemical changes from within the skin. Whether extrinsic or intrinsic, these factors result in visible signs of skin aging and damage, such as wrinkling, roughness and histological changes.
  • skin wrinkles are a reminder of the disappearance of youth. As a result, the elimination of wrinkles has become a concern for many people.
  • Extrinsic or intrinsic factors may result in the thinning and general degradation of the skin. For example, as the skin naturally ages, there is a reduction in the cells and the blood vessels that supply the skin. There is also a flattening of the dermal-epidermal junction that results in weaker mechanical resistance of this junction. See, for example, Oikarinen, "The Aging of Skin: Chronoaging Versus Photoaging,” Photodermatol. Photoimmunol. Photomed., vol. 7, pp. 3-4, 1990 .
  • the epidermis has a cell renewal system in which fully differentiated cells are continually shed from the skin surface and replaced by new cells formed within the germative cell layers of the skin. With increasing age, cell renewal rates decrease, leading to the development of coarse, sallow skin.
  • Skin also contains an elaborate network of elastin fibers that is responsible for maintaining its elastic properties. With excessive exposure to sunlight the elastic fiber system becomes hyperplastic, disorganized and ultimately disrupted. This process is known as actinic elastosis and it is a principal cause of wrinkling, discoloration and laxity of the skin in the exposed areas of the body. As new fibroblasts, endothelial cells and keratinocytes form, the skin can repair itself. However, the skin becomes less able to do so as it ages. Therefore, agents that can accelerate the growth and repair of prematurely aged skin are needed. Wound healing may also be accelerated by increased cellular proliferation and migration of certain cell types.
  • the mechanisms involved in wound healing are often divided into four phases: hemostasis, inflammation, proliferation and maturation.
  • leucocytes accumulate to combat bacteria and the permeability of blood vessel walls increases, leading to swelling. If an infection does not develop the number of leucocytes diminishes.
  • Monocytes replace the leukocytes. Macrophages and lymphocytes release growth factors (cytokines) as well as a number of chemical substances, such as histamine, serotonin, and prostaglandins. These substances help regulate the wound healing process.
  • cytokines growth factors
  • histamine histamine
  • serotonin prostaglandins
  • Fibroblasts become dominant after about a week, the inflammation decreases and the strength of the tissues around the wound site increases rapidly.
  • collagen is laid down and scar tissue is formed.
  • This maturation phase might go on for a long time, during which time, tissues of various types are regenerated.
  • the supply of different vitamins and trace elements as well as nutrients should be sufficient as well as the oxygen supply.
  • Anti-wrinkle treatments range from cosmetic creams and moisturizers to various forms of cosmetic surgery.
  • certain skin care compositions are available on the market, such compositions do not effectively stimulate the healing, growth, turnover and overall health of new skin tissues.
  • formulations that not only improve the appearance but also the health of skin.
  • such formulations would ideally provide a range of useful activities such as, for example, wound closure, wound healing, skin renewal, skin rejuvenation, scar reduction, soothing rashes, eliminating wrinkles and reducing the signs of aging.
  • the compositions of the invention can promote wound closure, speed up cellular turnover and stimulate cellular proliferation of mammalian fibroblasts or keratinocytes. Not only can these compositions stimulate cell growth, turnover and the repair of skin and gum tissues, but they can also stimulate collagen production and fibronectin production in mammalian fibroblasts.
  • compositions suitable for use in the treatment of the dermis comprising a dermatologically acceptable carrier, an effective amount of a salicylate compound and an effective amount of a jasmonic acid compound, a gibberellic acid compound, and a zeatin compound.
  • a dermatologically acceptable carrier an effective amount of a salicylate compound and an effective amount of a jasmonic acid compound, a gibberellic acid compound, and a zeatin compound.
  • Such a composition can promote wound closure.
  • Such compositions are useful for treating any type of wound, including fresh wounds, abrasions, puncture wounds, chronic wounds and wounds that have been slow to close.
  • Such a composition can also stimulate fibronectin production in mammalian fibroblasts.
  • Such compositions are useful for treating wounds, stimulating gum tissue growth and for reversing the effects of aging on skin.
  • the invention also provides use of a dermatologically acceptable carrier, an effective amount of a salicylate compound and an effective amount of a j asmonic acid compound, a gibberellic acid compound, a zeatin compound or a combination thereof; for the preparation of a composition for use in promoting healthy skin development in a mammal, wherein the composition can stimulate fibronectin production in mammalian fibroblasts or wound closure in the dermis of the mammal.
  • the invention also provides use of a dermatologically acceptable carrier, an effective amount of a salicylate compound and an effective amount of a jasmonic acid compound, a gibberellic acid compound, a zeatin compound or a combination thereof; for the preparation of a composition for use in stimulating fibronectin production in mammalian fibroblasts.
  • the invention also provides use of a dermatologically acceptable carrier, an effective amount of a salicylate compound and an effective amount of a jasmonic acid compound, a gibberellic acid compound, a zeatin compound or a combination thereof; for use in the preparation of a composition for promoting wound closure in a mammal, wherein the composition can stimulate cellular proliferation of mammalian fibroblasts or keratinocytes.
  • the invention also provides use of a dermatologically acceptable carrier, an effective amount of a salicylate compound and an effective amount of a jasmonic acid compound or a gibberellic acid compound or a combination thereof; for use in the preparation of a composition for promoting skin cell renewal in a mammal, wherein the composition can increase the rate of skin cell renewal in a mammal, wherein the jasmonic acid compound is a compound of any formulae VI, VII, VIII or IX: wherein:
  • the invention relates to compositions for use in promoting skin cell renewal comprising a dermatologically acceptable carrier, an effective amount of a salicylate compound, and an effective amount of a jasmonic acid compound, a gibberellic acid compound, a zeatin compound or a combination thereof, according to claim 24.
  • compositions suitable for use in the treatment of the dermis comprising a dermatologically acceptable carrier, an effective amount of a salicylate compound and an effective amount of jasmonic acid, a gibberellic acid compound, a zeatin compound or a combination thereof.
  • the invention provides a composition comprising:
  • the effective amount of the jasmonic acid compound, the gibberellic acid compound or the zeatin compound is a concentration of about 0.001 micromolar to about 10 millimolar. In other embodiments, the effective amount of the jasmonic acid compound, the gibberellic acid compound or the zeatin compound is a concentration of about 1 micromolar to about 5 millimolar. In further embodiments the effective amount of the jasmonic acid compound, the gibberellic acid compound or the zeatin compound is a concentration of about 0.01% to about 50% of the composition.
  • compositions can have one or more additional ingredients.
  • additional ingredients such as desquamation compounds, anti-acne compounds, anti-wrinkle compounds, vitamin B 3 compounds, vitamin E compounds, retinoid compounds, hydroxy acid compounds, anti-oxidant compounds, radical scavengers, chelating agents, flavonoid compounds, anti-inflammatory agents, anti-cellulite agents, topical anesthetics, tanning compounds, skin lightening agents, skin healing compounds, anti-microbial compounds, antifungal compounds, sunscreen compounds, particulate material, moisturizers, or thickening agents.
  • vitamin E compounds examples include tocopherol, tocopherol acetate, a tocopherol ester or a mixture thereof.
  • retinoid compounds examples include retinol, retinal, retinol ester, retinyl propionate, retinoic acid, retinyl palmitate, or a mixture thereof.
  • Particulate materials that may be employed include mica, mica treated with barium sulfate and TiO 2 , silica, nylon, polyethylene, talc, styrene, polypropylene, ethylene/acrylic acid copolymer, sericite, aluminum oxide, silicone resin, barium sulfate, titanium dioxide, iron oxide, bismuth oxychloride, calcium carbonate, cellulose acetate, polymethyl methacrylate, or a mixture thereof.
  • Sunscreens that can be used include, for example, a metallic oxide selected from the group consisting of titanium dioxide having an average primary particle size of from about 15 nm to about 100 nm, zinc oxide having an average primary particle size of from about 15 nm to about 150 nm, zirconium oxide having an average primary particle size of from about 15 nm to about 150 nm, iron oxide having an average primary particle size of from about 15 nm to about 500 nm, or a mixture thereof.
  • Other sunscreens that may be used include octylmethoxycinnamate, octyl salicylate, terephthalyidene dicamphor sulfonic acid, avobenzone, octocrylene, or a mixture thereof.
  • compositions for use in wound closure, increasing cell proliferation, promoting skin renewal and for stimulating collagen and fibronectin production in the skin can also be used to reverse the effects of aging in all types and layers of skin tissues including the dermis, epidermis, keratinous tissues, mucosal tissues and the like. Such compositions are useful for treating wounds, stimulating gum tissue growth and for reversing the effects of aging on skin.
  • the compositions of the invention can contain an effective amount of a salicylate compound, a j asmonic acid compound, a gibberellic acid compound, a zeatin compound or combinations thereof as well as acceptable carriers and other ingredients.
  • compositions or components thereof are suitable for use in contact with mammalian skin tissue without undue toxicity, incompatibility, instability, allergic response, and the like.
  • dermis refers to the layer of skin that forms the foundation upon which the epidermis lies.
  • the primary cellular components of the dermis are the dermal fibroblasts that exist in a sea of extracellular matrix within the dermis.
  • epidermis refers to the layer of skin over the dermis.
  • the epidermis is a stratified squamous epithelium, composed primarily of keratinocytes. Keratinocytes within the epidermis are organized into four layers including the basal, spinous, granular, and cornified layers.
  • the hexoses employed in the invention include any six-membered D or L saccharide. Such hexoses include allose, altrose, glucose, mannose, galose, idose, galactose and talose. The hexose utilized may also be a deoxy hexose.
  • keratinous tissue refers to keratin-containing layers disposed as the outermost protective covering of mammals (e.g., humans, dogs, cats, etc.) that includes, skin, lips, hair, toenails, fingernails, cuticles, hooves, etc.
  • mucusal tissues refer to dermal layers that secrete mucus, including, for example, the mouth, the throat, the genitalia, particularly the external female genitalia, and the like.
  • pentose refers to any five-membered D or L saccharide or sugar. Such pentoses include ribose, arabinose, xylose and lyxose. The pentose utilized may also be a deoxy pentose.
  • promote faster cell turnover refers to the movement of cells from the basement membrane region of the dermis through the layers of the epidermis until they enucleate and are sloughed from the surface of the skin.
  • the rate of cellular turnover can be measured as described herein, for example, in the Examples.
  • safe and effective amount means an amount of a compound or composition sufficient to significantly induce a positive benefit, such as a positive appearance of the skin or a positive feel to the skin, but low enough to avoid serious side effects, i.e., to provide a reasonable benefit to risk ratio, within the scope of sound judgment of the skilled artisan.
  • sagging means the laxity, slackness, or the like condition of skin that occurs as a result of loss of, damage to, alterations to, and/or abnormalities in dermal elastin.
  • skin refers to the outer covering of an animal body; the outermost layer of skin is called the epidermis, the layer beneath the epidermis is called the dermis.
  • smoothing and softening as used herein mean altering the surface of the skin and/or keratinous tissue such that its tactile feel is improved.
  • “Signs of skin aging” include, all outwardly visible or tactilely perceptible manifestations as well as any other macro or micro effects due to skin aging. Such signs may be induced or caused by intrinsic factors or extrinsic factors, e.g., chronological aging and/or environmental damage.
  • sugar residue means any sugar available to one of skill in the art.
  • a sugar residue can be a hexose or a pentose.
  • topical application means to apply or spread the compositions of the present invention onto the surface of the skin tissue or within a wound.
  • Skin which is the external covering of the body, has two components: the epidermis that contains four layers and the dermis, also referred to as the corium, cutis, derma, or true skin, which contains a superficial papillary layer and a deep reticular layer.
  • the dermis whose primary cellular components are fibroblasts, forms the foundation upon which the epidermis lies.
  • Dermal fibroblasts the primary cellular component of the dermis, exist in a sea of extracellular matrix. These matrix components not only physically support the overlying layers, but are also involved in biochemical signaling pathways. Clark, E. A. and J. S. Brugge, Science 268: 233-9 (1995 ).
  • fibroblasts In addition to secreting matrix components, fibroblasts also secrete a spectrum of growth factors, which act on the overlying epidermis. Mass-Szabowski and N. E. Fusenig, J. Invest. Dermatol. 107: 849-55 (1996 ); Smola, H. et al., J. Cell Biol. 122: 417-29 (1993 ).
  • the epidermis is a stratified squamous epithelium having many keratinocytes. Keratinocytes within the epidermis are organized into four layers based on morphological and biochemical properties; these are the basal, spinous, granular, and cornified layers. Eckert, R. L. et al., Physiol Rev 77: 397-424 (1997 ). The basal layer rests atop the dermis and is in direct contact with the specialized extracellular matrix proteins of the basement membrane. Basal keratinocytes have the ability to replicate and are the source of all suprabasal keratinocytes within the epidermis. As basal cells divide, certain daughter cells lose contact with the basement membrane. These cells assume a suprabasal position and continue movement upward through the layers of the epidermis until they enucleate and are sloughed from the surface of the skin, a process known as terminal differentiation.
  • Collagen constitutes about 80% of the dry weight of the dermis and is the major fibrillar component of human skin.
  • the dermis is composed of connective tissue that contains lymphatics, nerves and nerve endings, blood vessels, sebaceous and sweat glands, and elastic fibers that provide the elastic properties of the skin.
  • the mature fiber contains about 90% elastin and two glycosaminoglycans are present at concentrations of about 2% and 0.1%, respectively (see, e.g., Braverman (1982) J. Invest. Dermatol, 78:434-443 ).
  • the coarse branching fibers are entwined with collagen fiber bundles in the reticular dermis. The fibers rise from the deeper layers of the papillary layer of the dermis and, as they rise towards the epidermis, they split repeatedly become finer and form a network.
  • Aging skin is characterized by initial elastogenesis followed by a slow spontaneous progressive degradation of the elastic fibers that leads to laxity and wrinkling.
  • Studies of skin from subjects of various ages indicate that the degradation of elastic fibers that begins about age 30 and becomes marked after age 70 as a major feature of aging skin.
  • Fibroblasts synthesize components that are required for maintenance of the structural, functional and cosmetic integrity of the skin and the structural and functional integrity of other surface tissues covered by epithelia.
  • collagen and elastin are fibrous proteins responsible for the three-dimensional architecture of skin and the other surface tissues
  • fibronectin which is a protein responsible for cell anchorage and maintenance of cell morphology
  • proteinaceous growth factors essential for the maintenance of epithelia and basal cell layers and connective tissue layers underlying them.
  • Available evidence indicates that protein biosynthetic activity of fibroblasts decreases significantly with age. For example, the rate of collagen synthesis at about 70% of life expectancy for human fibroblasts in culture is only about 50% of that of such fibroblasts at less than 20% of life expectancy.
  • Intrinsic aging includes changes that occur as a result of endogenous factors and genetically programmed senescence, including epidermal and dermal atrophy.
  • Photoaging results from long-term exposure to UV (ultraviolet) radiation, primarily from the sun. Ultraviolet exposure is also associated with tumor induction and other skin pathologies.
  • UVB 280-315 nm
  • UVA 315-400 nm
  • UVB causes erythema, skin cancer and dermal connective tissue damage.
  • UVA also causes erythema and is carcinogenic at higher doses.
  • Low doses 2.5 minimal erythemic doses (MEDs)
  • MEDs minimal erythemic doses
  • compositions of jasmonic acid, gibberellic acid, zeatin, salicylates or combinations thereof can increase cellular turnover in skin, promote cellular proliferation, facilitate wound healing, reduce scarring, sooth rashes and help to eliminate wrinkles and other signs of aging.
  • compositions of the present invention contain a safe and effective amount of a salicylate.
  • salicylates for use in the compositions of the present invention include salicylic acid, acetylsalicylic acid, and other salicylic acid derivatives.
  • salicylic acid and the synthetic and naturally occurring derivatives of salicylic acid can be used in the compositions and uses of the present invention.
  • alkyl groups employed in these salicylate compounds have about one to twenty carbon atoms, although in some embodiments lower alkyl groups are used, for example, alkyl groups with about one to eight carbon atoms. Alkyl groups with even lower numbers of carbon atoms can also be used, for example, alkyl groups with one to six carbon atoms, or one to three carbon atoms.
  • salicylic acid is employed in the compositions of the invention.
  • Salicylic acid is a compound of formula I wherein R 1 is COOH and R 2 is OH.
  • acetylsalicylic acid is employed in the compositions of the invention.
  • Acetylsalicylic acid is a compound of formula I wherein R 1 is COOH and R 2 is OCOCH 3 .
  • salicyclic acid or its derivatives can be used in an amount of from about 0.00 1 % to about 50%, or from about 0.01% to about 20%, or from about 0.01% to about 10%, or from about 0.05% to about 5%, or from about 0.05% to about 2% of the composition.
  • in situ concentrations of acetylsalicylic acid or salicylic acid that range from about 10 -4 M to about 10 -6 M are effective for increasing cell proliferation and stimulating the production of collagen in mammalian skin.
  • Gibberellic acid comprises a class of compounds that is also referred to as gibberellins.
  • Gibberellins are plant hormones that affect a wide variety of processes throughout the life cycle of plants, including seed germination, stem elongation, flower induction, anther development, and seed and pericarp growth.
  • Gibberellins are tetracyclic diterpenoid acids found in fungi and higher plants having the ent-gibberellane ring system shown in the following structure (II).
  • Gibberellins were first isolated by Japanese researchers in the 1930s from cultures of the fungus Gibberella fujikuroi ( Fusarium moniliforme ). Gibberellins are secondary metabolites that have since been shown to be present in other fungal species, in some ferns, and in many gymnosperms and angiosperms. Of the 121 known gibberellins, 96 have been identified only in higher plants, 12 are present only in Gibberella, and 12 are present in both. As observed in Gibberella , many different gibberellins can be present in individual angiosperms.
  • gibberellins Two main types exist: the C 20 -gibberellins, which have 20 carbon atoms (structure III, below), and the C 19 -gibberellins, in which the twentieth carbon atom has been lost due to metabolism (structure IV, below).
  • the ent-gibberellane ring system can contain many structural modifications, accounting for the large number of known gibberellins.
  • Naturally occurring gibberellins with identified structures are allocated an "A number" ( MacMillan et al. (1968) Nature 217:170-171 ).
  • 126 naturally occurring gibberellins of plant and fungal origin are known.
  • Current structural information on gibberellins can be found at the website plant-hormones.bbsrc.ac.uk/gibberellin_information2.htm.
  • Variations in gibberellin structure arise in several ways.
  • Carbon-20 can exist in different oxidative states, for example, methyl (--CH 3 ), hydroxymethyl (--CH 2 OH) aldehyde (--CHO), or carboxylic acid (--COOH).
  • the position and/or stereochemistry of substituent groups can affect the biochemical and physiological significance of the molecules.
  • Substituent groups positioned above the ring plane are said to be in the ⁇ -configuration; their bonding to the ring is designated by a solid, elongated triangle.
  • Substituent groups positioned below the ring plane are said to be in the a-configuration; their bonding to the ring is designated by a dashed, elongated triangle.
  • the attachment of substituent groups in the plane of the ring system is indicated by a straight line.
  • Gibberellins can exist as conjugates, for example with a hexose or pentose molecule such as glucose.
  • An ether or an ester linkage may link such a glucose molecule to the gibberellin.
  • Such conjugation may temporarily or permanently inactivate the activity of a gibberellin within a plant.
  • gibberellins The biological activity of different gibberellins varies, and various gibberellins within a plant can be precursors, biosynthetic intermediates, or deactivation products of active gibberellins.
  • Three structural features are commonly associated with gibberellin biological activity: a 3-hydroxyl group, a 7-carboxyl group, and a lactone ring.
  • a compound possessing the ent-gibberellane ring system but lacking one or more of these structural features can be considered a gibberellin precursor, an intermediate, or a derivative.
  • compositions and uses of the invention generally employ active forms of gibberellic acids, gibberellic acid precursors, gibberellic acid intermediates or gibberellic acid derivatives, for example, those having structures related to formulae III and IV as described above.
  • the gibberellins employed can also have double bonds within the ring structure at different positions.
  • the gibberellic acids can have any of formulae V, Va, or Vb.
  • Gibberellin having formula V is often referred to as Gibberellin A 3 .
  • Gibberellin having formula Va is often referred to as Gibberellin A 4 .
  • Gibberellin having formula Vb is often referred to as Gibberellin A 7 .
  • gibberellic acids or their derivatives can be used in an amount of from about 0.001% to about 50%, or from about 0.01 % to about 20%, or from about 0.01% to about 10%, or from about 0.05% to about 5%, or from about 0.05% to about 2% of the composition.
  • in situ concentrations of an active gibberellic acid ranging from about 10 -4 M to about 10 -6 M are effective for increasing cell proliferation and stimulating the production of collagen in mammalian skin.
  • Compositions having about 0.5 % gibberellic acid are shown herein to promote skin turnover.
  • Jasmonic acid compounds employed in the invention include jasmonic acid and jasmonic acid derivatives available to one of skill in the art. Such compounds include jasmonic acid, methyl jasmonate and their isomers. In the present invention jasmonic acid and jasmonic acid derivatives used also include synthetic and natural stereoisomers of jasmonic acid, dihydrojasmonic acid, hydroxy jasmonic acid and dihydro-hydroxy jasmonic acid. Further examples of jasmonic acid derivatives that may be used in the invention include compounds having any one of formulae VI, VII, VIII , or IX. wherein:
  • alkyl groups employed in these jasmonic acid compounds have about one to twenty carbon atoms, although in some embodiments lower alkyl groups are used, for example, alkyl groups with about one to eight carbon atoms. Alkyl groups with even lower numbers of carbon atoms can also be used, for example, alkyl groups with one to six, or one to three carbon atoms.
  • jasmonic acid is employed in the compositions of the invention.
  • Jasmonic acid is a compound of formula VI wherein R 3 is C 2 H 5 and R 4 is COOH.
  • Another jasmonic acid compound employed in the invention is a compound of formula VII. wherein:
  • dihydrojasmonic acid is employed in the compositions of the invention.
  • Dihydrojasmonic acid is a compound of formula VII wherein R 3 is C 2 H 5 and R 4 is COOH.
  • Another jasmonic acid compound employed in the invention is a compound of formula VIII wherein:
  • hydroxyjasmonic acid is employed in the compositions of the invention.
  • Hydroxyjasmonic acid is a compound of formula VIII wherein R 3 is C 2 H 5 and R 4 is COOH.
  • Another jasmonic acid compound employed in the invention is a compound of formula IX. wherein:
  • dihydro-hydroxyjasmonic acid is employed in the compositions of the invention.
  • Dihydro-hydroxyjasmonic acid is a compound of formula IX wherein R 3 is C 2 H 5 and R 4 is COOH.
  • jasmonic acids or jasmonic acid derivatives can be used in an amount of from about 0.001% to about 50%, or from about 0.01 % to about 20%, or from about 0.01 % to about 10%, or from about 0.05% to about 5%, or from about 0.05% to about 2% of the composition.
  • in situ concentrations of jasmonic acid ranging from about 10 -4 M to about 10 -6 M are effective for increasing cell proliferation and stimulating the production of collagen in mammalian skin.
  • solutions of jasmonic acid ranging from about 0.001 % to about 1.0% jasmonic acid are effective for promoting wound closure.
  • solutions of about 0.025% jasmonic acid are effective for promoting skin turnover and renewal.
  • Zeatin compounds employed in the invention include the cis and trans isomers of zeatin and the cis and trans isomers of zeatin derivatives available to one of skill in the art.
  • Such zeatin compounds and zeatin derivatives can be natural and synthetic derivatives of the compounds provided by formula X below.
  • zeatin is employed in the compositions of the invention.
  • Zeatin is a compound of formula X wherein R 5 is 3-hydroxymethyl-3-methylallyl, and R 6 is H.
  • zeatin or its derivatives can be used in an amount of from about 0.001% to about 50%, or from about 0.01% to about 20%, or from about 0.01% to about 10%, or from about 0.05% to about 5%, or from about 0.05% to about 2% of the composition.
  • in situ concentrations of zeatin ranging from about 10 -4 M to about 10 -6 M are effective for increasing cell proliferation and stimulating the production of collagen in mammalian skin.
  • compositions and uses of the invention are useful for stimulating cellular proliferation, increasing skin turnover, promoting wound healing and/or for stimulating collagen or fibronectin production in cells within skin tissues.
  • Such proliferation, turnover, healing and collagen/fibronectin production can therapeutically improve visible and/or tactile discontinuities in mammalian skin, including discontinuities in skin texture and color.
  • the apparent diameter of pores can decrease, the apparent height of tissue immediately proximate to pore openings approaches that of the interadnexal skin, the skin tone/color becomes more uniform, and/or the length, depth, and/or other dimension of lines and/or wrinkles are decreased.
  • compositions of the present invention are also useful for use in regulating the condition of skin and especially for regulating skin tissue condition.
  • Regulation of skin conditions namely mammalian and, in particular, human skin conditions, is often required due to conditions that may be induced or caused by factors internal and/or external to the body. Examples include, environmental damage, radiation exposure (including ultraviolet radiation), chronological aging, menopausal status (e.g., post-menopausal changes in skin), stress, diseases, etc.
  • Regulating skin condition includes prophylactically regulating and/or therapeutically regulating the skin condition. Regulating the skin condition may involve one or more of the following benefits: increasing the rate of skin renewal, thickening the skin (i.e., building the epidermis, dermis, sub-dermal, subcutaneous fat, or underlying muscle layers of the skin) and, where applicable, the keratinous layers of the nail and hair shaft, to reduce skin atrophy.
  • compositions and uses of the invention can also increase the convolution of the dermal-epidermal border (also known as the rete ridges), prevent loss of skin elasticity resulting from loss, damage and/or inactivation of functional skin elastin, prevent conditions such as elastosis, sagging, loss of skin recoil from deformation; non-melanin skin discoloration such as under eye circles, blotching (e.g., uneven red coloration due to, e.g., rosacea) (hereinafter referred to as "red blotchiness"), sallowness (pale color), discoloration caused by telangiectasia or spider vessels.
  • red blotchiness uneven red coloration due to, e.g., rosacea
  • prophylactically regulating skin condition also includes delaying, minimizing and/or preventing visible and/or tactile discontinuities in skin (e.g., texture irregularities in the skin which may be detected visually or by feel).
  • therapeutically regulating skin condition includes ameliorating, e.g., healing, diminishing, minimizing and/or effacing, discontinuities in skin.
  • compositions for use in stimulating cellular proliferation, cellular renewal, collagen production or fibronectin production in mucosal tissues like the gum tissues are useful for use in treating or preventing a variety of dental and oral conditions, including gum recession, gingivitis and gum disease.
  • These compositions can contain an effective amount of a salicylate compound, a jasmonic acid compound, a gibberellic acid compound, a zeatin compound or a combination thereof as well as an orally acceptable carrier and other ingredients.
  • Such compositions can be formulated as a mouthwash, a toothpaste, a gel for use in a dental tray that can cup the teeth or an adhesive that can stick to tooth or gum surfaces.
  • the carrier will include a tackifying agent and a solvent, which together yield a sticky matrix material.
  • the matrix material can be sufficiently sticky to enable a dental tray to be held and retained against a person's teeth. Suitable sticky matrix materials are preferably viscous and do not readily dissolve in saliva.
  • Various tackifying agents are available and the selection of the tackifying agent can readily be made by one of skill in the art.
  • One tackifying agent that can be used to form a sticky and viscous matrix material comprises carboxypolymethylene, for example, CARBOPOL 934P.
  • Carboxypolymethylene can be used to form a glue-like dental composition that itself can act as an adhesive in holding a comfortable, non-self-retaining dental tray against a person's teeth.
  • the use of carboxypolymethylene eliminates the need to use dental trays that are self-retaining (i.e., typically trays that are rigid and which mechanically interlock over a person's teeth or gums and which are intended for use with less sticky compositions). See, e.g., U.S. Patent 6,309,625 .
  • the dental compositions of the present invention can include carboxypolymethylene in a concentration in a range from about 0.5% to about 25% by weight of the dental composition, or in a range from about 2% to about 12% and or in a range from about 3% to about 10%.
  • carboxypolymethylene in a concentration in a range from about 0.5% to about 25% by weight of the dental composition, or in a range from about 2% to about 12% and or in a range from about 3% to about 10%.
  • carboxypolymethylene in a concentration in a range from about 0.5% to about 25% by weight of the dental composition, or in a range from about 2% to about 12% and or in a range from about 3% to about 10%.
  • concentration of carboxypolymethylene may be adjusted to achieve a desired level of any or all of these properties. Increased stickiness assists in retaining the preferred dental trays against a person's teeth.
  • compositions can be made less adhesive and tacky if desired, particularly is applied directly without a dental tray.
  • carboxypolymethylene be mixed with a suitable solvent before attempting to add other components that are less compatible with carboxypolymethylene, such as water.
  • suitable solvents for use with carboxypolymethylene include glycerin, other polyhydric alcohols, polyalkylene glycols and other polyols, and the like. Glycerin appears to enable larger quantities of carboxypolymethylene to be dispersed in water.
  • the concentration of glycerin, polyol, or like substance utilized as a solvent in the dental compositions be added in a range from about 15% to about 85% by weight of the dental compositions, more preferably in a range from about 25% to about 75% by weight, and most preferably in a range from about 30% to about 65% by weight. It should be understood, however, that the actual amount of carboxypolymethylene is not critical for obtaining a sticky, viscous dental composition.
  • the sticky matrix material may include other tackifying components that in combination with, or in lieu of some or all of, the carboxypolymethylene will yield a gum stimulating composition having the desired level of stickiness needed to hold a preferred, comfortable-fitting dental tray in place over a person's teeth.
  • Other synthetic polymers and/or natural gums, proteins, or other gel-forming admixtures can be used so long as they yield a sticky gum stimulating composition.
  • tackifying and thickening agents include gums such as xanthan gum, talha gum, tragacanth gum, locust bean gum, guar gum, Irish moss gum, ghatti gum, furcelleran gum, carrageenan gum, arabic gum, alginic acid gum, agar gum, alginate gum.
  • Another suitable tackifying agent is sold as PEMULENTM, a proprietary compound from B. F. Goodrich, or a compositional or chemical equivalent thereof.
  • PEMULENTM includes a significant quantity of a polyacrylic copolymer that has a slightly hydrophobic end and a strongly hydrophilic end.
  • suitable tackifying agents include polyethylene oxides such as POLYOXTM sold by Union Carbide. These tackifying agents may be present in the same ranges as discussed above in relation to carboxypolymethylene
  • One of skill in the art may include other active dental agents to treat or prevent other types of dental and/or gum problems.
  • active dental agents such as, in conjunction with the gum-stimulating components of the invention, such a skilled artisan may provide anti-cariogenic and anti-demineralizing agents such as fluoride salts, more particularly sodium monofluorophosphate, sodium fluoride, and stannous fluoride.
  • fluoride salts more particularly sodium monofluorophosphate
  • sodium fluoride sodium fluoride
  • stannous fluoride stannous fluoride
  • the fluoride will be included in a range from about 0% to about 1% by weight of the dental composition, more preferably in a range from about 0.1% to about 0.5% by weight.
  • Antimicrobial agents e.g., for fighting gum disease, may be included in conjunction with the gum stimulating components of the invention.
  • useful antimicrobial agents include chlorohexidine, tetracycline, cetyl pyridinium chloride, benzalkonium chloride, cetyl pyridinium bromide, methyl benzoate, and propyl benzoate.
  • the antimicrobial agents are preferably included in an amount in a range from about 0% to about 15% within the gum stimulating composition, or in a range from about 1% to about 5% by weight.
  • One method of dispensing sticky and viscous gum stimulating compositions within the scope of the present invention is by means of a syringe.
  • Squeezable tubes and other similar dispensing devices may also be used to dispense the compositions.
  • the gum stimulating compositions are sufficiently viscous that they do not easily settle or spread once dispensed, but will generally remain as a single extruded strand or bead of gum stimulating composition, for example, along the gum line.
  • bottles, tubes or other dispensing means known in the art may be used, particularly where the gum stimulating composition has lower viscosity, low stickiness, and does not include a thickening agent.
  • the invention provides a unit dose of the gum stimulating compositions in a syringe or similar dispensing device.
  • the person can load the precise amount of gum stimulating composition onto the dental tray for each treatment period.
  • the dentist is also able to monitor how many doses the person has received and used.
  • the gum stimulating compositions can be applied directly to the person's teeth without a dental tray, or a less viscous and sticky stimulating composition according to the invention may be used in conjunction with self-retaining trays known in the art.
  • a given gum stimulating composition may be able to retain the dental tray against a person's teeth for, e.g., 10 hours or more, that composition could certainly be used within the scope of the present invention for any desired time period, such as for 15 minutes, one hour, or any desired time duration.
  • the dental trays can be used at night during a person's sleep.
  • compositions of the present invention may contain one or more additional skin care or gum care active ingredients.
  • the additional components should be suitable for application to skin tissue, particularly when the composition is to be in contact with human keratinous tissue.
  • the additional ingredients incorporated into the composition are suitable for contact with human skin tissue and do out have undue toxicity, incompatibility, instability, allergic response, and the like within the scope of sound medical judgment.
  • the CTFA Cosmetic Ingredient Handbook, Second Edition (1992 ) describes a wide variety of nonlimiting cosmetic and pharmaceutical ingredients commonly used in the skin care industry, which are suitable for use in the compositions of the present invention.
  • these ingredient classes include: abrasives, absorbents, aesthetic components such as fragrances, pigments, colorings/colorants, essential oils, skin sensates, astringents (clove oil, menthol, camphor, eucalyptus oil, eugenol, menthyl lactate, witch hazel distillate), anti-acne agents, anti-caking agents, antifoaming agents, antimicrobial agents, antioxidants, binders, biological additives, buffering agents, bulking agents, chelating agents, chemical additives, colorants, cosmetic astringents, cosmetic biocides, denaturants, drug astringents, external analgesics, film formers, opacifying agents, pH adjusters, propellants, reducing agents, sequestrants, skin bleaching and lightening
  • the active ingredients useful herein can be categorized by the benefit they provide or by their postulated mode of action. However, it is to be understood that the active ingredients useful herein can in some instances provide more than one benefit or operate via more than one mode of action. Therefore, classifications herein are made for the sake of convenience and are not intended to limit the active to that particular application or applications listed.
  • a safe and effective amount of a desquamation compound may be added to the compositions of the present invention, or from about 0.1 % to about 10%, or from about 0.2% to about 5%, or from about 0.5% to about 4%, by weight of the composition.
  • Desquamation compounds enhance the skin appearance benefits of the present invention. For example, the desquamation compounds tend to improve the texture of the skin (e.g., smoothness).
  • One desquamation system that is suitable for use herein contains sulfhydryl compounds and zwitterionic surfactants and is described in U.S. Patent 5,681,852, to Bissett , incorporated herein by reference. Zwitterionic surfactants such as described in these applications are also useful as desquamatory agents herein, with cetyl betaine being particularly desirable.
  • compositions of the present invention may contain a safe and effective amount of one or more anti-acne active ingredients.
  • useful anti-acne ingredients include resorcinol, sulfur, benzoyl peroxide, erythromycin, zinc, and the like. Further examples of suitable anti-acne compounds are described in further detail in U.S. Patent 5,607,980, issued to McAtee et al, on March 4, 1997 .
  • compositions of the present invention may further contain a safe and effective amount of one or more anti-wrinkle compounds or anti-atrophy compounds.
  • anti-wrinkle/anti-atrophy compounds suitable for use in the compositions of the present invention include sulfur-containing D and L amino acids and their derivatives and salts, particularly the N-acetyl derivatives, a preferred example of which is N-acetyl-L-cysteine; thiols (e.g. ethane thiol); phytic acid, lipoic acid; lysophosphatidic acid, skin peel agents (e.g., phenol and the like), vitamin B 3 compounds and retinoids that enhance the health and/or appearance of skin tissues.
  • compositions of the present invention may contain a safe and effective amount of a vitamin B 3 compound.
  • the compositions can contain from about 0.01% to about 50%, or from about 0.1 % to about 10%, or from about 0.5% to about 10%, or from about 1% to about 5%, or from about 2% to about 5%, by weight of the composition, of the vitamin B 3 compound.
  • vitamin B 3 compound means a compound having the formula: wherein R 7 is --CONH 2 (e.g., niacinamide), --COOH (e.g., nicotinic acid) or --CH 2 OH (e.g., nicotinyl alcohol), derivatives thereof, and salts of any of the foregoing.
  • R 7 is --CONH 2 (e.g., niacinamide), --COOH (e.g., nicotinic acid) or --CH 2 OH (e.g., nicotinyl alcohol), derivatives thereof, and salts of any of the foregoing.
  • Exemplary derivatives of the foregoing vitamin B 3 compounds include nicotinic acid esters, including non-vasodilating esters of nicotinic acid (e.g., tocopheryl nicotinate), nicotinyl amino acids, nicotinyl alcohol esters of carboxylic acids, nicotinic acid N-oxide and niacinamide N-oxide.
  • nicotinic acid esters including non-vasodilating esters of nicotinic acid (e.g., tocopheryl nicotinate), nicotinyl amino acids, nicotinyl alcohol esters of carboxylic acids, nicotinic acid N-oxide and niacinamide N-oxide.
  • the vitamin compounds may be included as the substantially pure material, or as an extract obtained by suitable physical and/or chemical isolation from natural (e.g., plant) sources.
  • vitamin B 3 compounds are well known in the art and are commercially available from a number of sources, e.g., the Sigma Chemical Company (St. Louis, Mo.); ICN Biomedicals, Inc. (Irvin, Calif.) and Aldrich Chemical Company (Milwaukee, Wis.).
  • compositions of the present invention may also contain a retinoid.
  • retinoid includes all natural and/or synthetic analogs of Vitamin A or retinol-like compounds that possess the biological activity of Vitamin A in the skin as well as the geometric isomers and stereoisomers of these compounds.
  • the retinoid can, for example, be retinol, retinol esters (e.g., C 2 -C 22 alkyl esters of retinol, including retinyl palmitate, retinyl acetate, retinyl propionate), retinal, and/or retinoic acid (including all-trans retinoic acid and/or 13-cis-retinoic acid).
  • retinoids other than retinoic acid are used. These compounds are available in the art and are commercially available from a number of sources, e.g., Sigma Chemical Company (St. Louis, Mo.), and Boerhinger Mannheim (Indianapolis, Ind.). Other retinoids that are useful herein are described in U.S. Patent 4,677,120, issued Jun. 30, 1987 to Parish et al. ; U.S. Patent 4,885,311, issued Dec. 5, 1989 to Parish et al. ; U.S. Patent 5,049,584, issued Sep. 17, 1991 to Purcell et al. ; U.S. Patent 5,124,356, issued Jun. 23, 1992 to Purcell et al. ; and U.S.
  • Other suitable retinoids are tocopheryl-retinoate, tocopherol ester of cis- or trans-retinoic acid, adapalene (6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid), and tazarotene (ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl]nicotinate).
  • Desirable retinoids include retinol, retinyl palmitate, retinyl acetate, retinyl propionate, retinal and combinations thereof.
  • the retinoid may be included as the substantially pure material, or as an extract obtained by suitable physical and/or chemical isolation from natural (e.g., plant) sources.
  • the retinoid is substantially pure, or essentially pure.
  • compositions of this invention may contain a safe and effective amount of the retinoid, such that the resultant composition is safe and effective for regulating or improving the condition of skin tissues.
  • the compositions and uses of the invention can improve visible and/or tactile discontinuities in skin, or improve signs of skin aging.
  • the compositions preferably contain from about 0.005% to about 2%, or from about 0.01% to about 2%, retinoid.
  • Retinol can also be used in an amount of from about 0.01% to about 0.15%.
  • Retinol esters can be used in an amount of from or about 0.01 % to or about 2% (e.g., about 1%).
  • Retinoic acids can be used in an amount of from or about 0.01% to or about 0.25%.
  • Tocopheryl-retinoate, adapalene, and tazarotene can be used in an amount of from or about 0.01% to or about 2%.
  • compositions of the present invention contain both a retinoid and a vitamin B 3 compound
  • the retinoid can be used in the above amounts
  • the vitamin B 3 compound can be used in an amount of from or about 0.1 % to about 10%, or from about 2% to about 5%.
  • Peptides may be included in the compositions of the present invention in amounts that are safe and effective.
  • peptides refers to both the naturally occurring peptides and synthesized peptides. Also useful herein are naturally occurring and commercially available compositions that contain peptides.
  • Suitable dipeptides for use herein include Carnosine (beta-ala-his).
  • Suitable tripeptides for use herein include, gly-his-lys, arg-lys-arg, and his-gly-gly.
  • Preferred tripeptides and derivatives thereof include palmitoyl-gly-his-lys, which may be purchased as Biopeptide CLTM (100 ppm of palmitoyl-gly-his-lys commercially available from Sederma, France); Peptide CK (arg-lys-arg); Peptide CK+ (ac-arg-lys-arg-NH 2 ); and a copper derivative of his-gly-gly sold commercially as Iamin, from Sigma (St. Louis, Mo.).
  • Suitable tetrapeptides for use herein include Peptide E, arg-ser-arg-lys (SEQ ID NO:1).
  • Suitable pentapeptides for use herein include lys-thr-thr-lys-ser (SEQ ID NO:2).
  • a preferred commercially available pentapeptide derivative composition is MatrixylTM, which contains 100 ppm palmitoyl-lys-thr-thr-lys-ser (SEQ ID NO:3, commercially available from Sederma France).
  • Desirable peptides include pahnitoyl-lys-thr-thr-lys-ser, palmitoyl-gly-his-lys, beta-ala-his, their derivatives, and combinations thereof.
  • the peptide is selected from pahnitoyl-lys-thr-thr-lys-ser (SEQ ID NO:3), palmitoyl-gly-his-lys (SEQ ID NO:4), their derivatives, and combinations thereof.
  • the peptide is selected from palmitoyl-lys-thr-thr-lys-ser (SEQ ID NO:3) and derivatives thereof.
  • peptides When included in the present compositions, peptides can be present in amounts of from about 1x10 -6 % to about 10%, or from about 1x10 -6 % to about 0.1%, or from about 1x10 -5 % to about 0.01%, by weight of the composition. In certain compositions where the peptide is CarnosineTM, the compositions can contain from about 0.1 % to about 5%, by weight of the composition, of such peptides. In other embodiments wherein the peptide-containing compositions, MatrixylTM, and/or Biopeptide CLTM are included, the compositions can contain from about 0.1% to about 10%, by weight compositions, of MatrixylTM and/or Biopeptide CLTTM peptide-containing compositions.
  • compositions of the present invention may include a safe and effective amount of an anti-oxidant/radical scavenger.
  • the anti-oxidant/radical scavenger is especially useful for providing protection against ultraviolet radiation that can cause increased scaling or texture changes in the stratum corneum and against other environmental agents that can cause skin damage.
  • a safe and effective amount of an anti-oxidant/radical scavenger may be added to the compositions of the subject invention, for example, from about 0.1% to about 10%, or from about 1% to about 5%, of the composition.
  • Anti-oxidants/radical scavengers such as ascorbic acid (vitamin C) and its salts, ascorbyl esters of fatty acids, ascorbic acid derivatives (e.g., magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbyl sorbate), tocopherol (vitamin E), tocopherol sorbate, tocopherol acetate, other esters of tocopherol, butylated hydroxy benzoic acids and their salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (commercially available under the trade name TroloxTM), gallic acid and its alkyl esters, especially propyl gallate, uric acid and its salts and alkyl esters, sorbic acid and its salts, lipoic acid, amines (e.g., N,N-diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (e.g., glutathione),
  • anti-oxidants/radical scavengers are selected from tocopherol sorbate and other esters of tocopherol.
  • tocopherol sorbate for example, the use of tocopherol sorbate in topical compositions and applicable to the present invention is described in U.S. Patent 4,847,071 .
  • compositions of the present invention may also contain a safe and effective amount of a chelator or chelating agent.
  • chelator or “chelating agent” means an active agent capable of removing a metal ion from a system by forming a complex so that the metal ion cannot readily participate in or catalyze chemical reactions.
  • the inclusion of a chelating agent is useful for providing protection against ultraviolet radiation that can contribute to excessive scaling or skin texture changes and against other environmental agents that can cause skin damage.
  • a safe and effective amount of a chelating agent may be added to the compositions of the subject invention, for example, from about 0.1 % to about 10%, or from about 1% to about 5%, of the composition.
  • Exemplary chelators that are useful herein are disclosed in U.S. Patent 5,487,884 ; International Publication No. 91/16035, Bush et al., published Oct. 31, 1995 ; and International Publication No. 91/16034, Bush et al., published Oct. 31, 1995 .
  • the chelators used in compositions of the subject invention include, for example, furildioxime, furilmonoxime, and derivatives thereof.
  • compositions of the present invention may optionally contain a flavonoid compound.
  • Flavonoids are broadly disclosed in U.S. Pat. Nos. 5,686,082 and 5,686,367 .
  • Flavonoids suitable for use in the present invention are flavanones selected from unsubstituted flavanones, mono-substituted flavanones, and mixtures thereof; chalcones selected from unsubstituted chalcones, mono-substituted chalcones, di-substituted chalcones, tri-substituted chalcones, and mixtures thereof; flavones selected from unsubstituted flavones, mono-substituted flavones, di-substituted flavones, and mixtures thereof; one or more isoflavones; coumarins selected from unsubstituted coumarins, mono-substituted coumarins, di-substituted coumarin
  • substituted means flavonoids wherein one or more hydrogen atom of the flavonoid has been independently replaced with hydroxyl, C 1 -C 8 alkyl, C 1 -C 4 alkoxyl, O-glycoside, and the like or a mixture of these substituents.
  • suitable flavonoids include, but are not limited to, unsubstituted flavanone, mono-hydroxy flavanones (e.g., 2'-hydroxy flavanone, 6-hydroxy flavanone, 7-hydroxy flavanone, etc.), mono-alkoxy flavanones (e.g., 5-methoxy flavanone, 6-methoxy flavanone, 7-methoxy flavanone, 4'-methoxy flavanone, etc.), unsubstituted chalcone (e.g.
  • unsubstituted trans-chalcone mono-hydroxy chalcones (e.g., 2'-hydroxy chalcone, 4'-hydroxy chalcone, etc.), di-hydroxy chalcones (e.g., 2',4-dihydroxy chalcone, 2',4'-dihydroxy chalcone, 2,2'-dihydroxy chalcone, 2',3-dihydroxy chalcone, 2',5'-dihydroxy chalcone, etc.), and tri-hydroxy chalcones (e.g., 2',3',4'-trihydroxy chalcone, 4,2',4'-trihydroxy chalcone, 2,2',4'-trihydroxy chalcone, etc.), unsubstituted flavone, 7,2'-dihydroxy flavone, 3',4'-dihydroxy naphthoflavone, 4'-hydroxy flavone, 5,6-benzoflavone, and 7,8-benzoflavon
  • unsubstituted flavanone, methoxy flavanones, unsubstituted chalcone, 2',4-dihydroxy chalcone, and mixtures thereof are used in the compositions of the invention.
  • unsubstituted flavanone, unsubstituted chalcone (especially the trans isomer), and mixtures thereof are used in the compositions of the invention.
  • Flavonoids can be synthesized or obtained as extracts from natural sources (e.g., plants).
  • the naturally sourced material can also further be derivatized (e.g., an ester or ether derivative prepared following extraction from a natural source).
  • Flavonoid compounds useful herein are also commercially available from a number of sources, e.g., Indofine Chemical Company, Inc. (Somerville, N.J.), Steraloids, Inc. (Wilton, N.H.), and Aldrich Chemical Company, Inc. (Milwaukee, Wis.). Mixtures of such flavonoid compounds may also be used.
  • the flavonoid compounds can be present in the invention, for example, at concentrations of from about 0.01% to about 20%, more preferably from about 0.1 % to about 10%, and still more preferably from about 0.5% to about 5%.
  • a safe and effective amount of an anti-inflammatory agent may be added to the compositions of the present invention, for example, from about 0.1% to about 10%, or from about 0.5% to about 5%, of the composition.
  • the anti-inflammatory agent can enhance the appearance of the skin, for example, by contributing to a more uniform and acceptable skin tone or color.
  • the exact amount of anti-inflammatory agent to be used in the compositions will depend on the particular anti-inflammatory agent utilized since such agents vary widely in potency.
  • Steroidal anti-inflammatory agents including but not limited to, corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methyl
  • a second class of anti-inflammatory agents that is useful in the compositions includes the nonsteroidal anti-inflammatory agents.
  • a variety of compounds are encompassed by this group.
  • Anti-inflammatory and Anti-Rheumatic Drugs K. D. Rainsford, Vol. I-III, CRC Press, Boca Raton, (1985 ), and Anti-inflammatory Agents, Chemistry and Pharmacology, 1, R. A. Scherrer, et al., Academic Press, New York (1974 ).
  • composition invention examples include:
  • non-steroidal anti-inflammatory agents may also be employed, as well as the dermatologically acceptable salts and esters of these agents.
  • etofenamate a flufenamic acid derivative
  • ibuprofen, naproxen, flufenamic acid, etofenamate, aspirin, mefenamic acid, meclofenamic acid, piroxicam and felbinac are often used.
  • Ibuprofen, naproxen, ketoprofen, etofenamate, aspirin and flufenamic acid are frequently used.
  • agents are useful in uses of the present invention.
  • Such agents may suitably be obtained as an extract by suitable physical and/or chemical isolation from natural sources (e.g., plants, fungi, by-products of microorganisms) or can be synthetically prepared.
  • candelilla wax bisabolol (e.g., alpha bisabolol), aloe vera, plant sterols (e.g., phytosterol), Manjistha (extracted from plants in the genus Rubia, particularly Rubia Cordifolia), and Guggal (extracted from plants in the genus Commiphora, particularly Commiphora Mukul), kola extract, chamomile, red clover extract, and sea whip extract, may be used.
  • bisabolol e.g., alpha bisabolol
  • aloe vera e.g., plant sterols (e.g., phytosterol)
  • Manjistha extracted from plants in the genus Rubia, particularly Rubia Cordifolia
  • Guggal extracted from plants in the genus Commiphora, particularly Commiphora Mukul
  • kola extract chamomile
  • red clover extract and sea whip extract
  • Additional anti-inflammatory agents useful herein include compounds of the Licorice (the plant genus/species Glycyrrhiza glabra) family, including glycyrrhetic acid, glycyrrhizic acid, and derivatives thereof (e.g., salts and esters).
  • Suitable salts of the foregoing compounds include metal and ammonium salts.
  • Suitable esters include C 2 -C 24 saturated or unsaturated esters of the acids, or C 10 -C 24 , or C 16 -C 24 .
  • oil soluble licorice extract examples include oil soluble licorice extract, the glycyrrhizic and glycyrrhetic acids themselves, monoammonium glycyrrhizinate, monopotassium glycyrrhizinate, dipotassium glycyrrhizinate, 1-beta-glycyrrhetic acid, stearyl glycyrrhetinate, and 3-stearyloxyglycyrrhetinic acid, and disodium 3-succinyloxy-beta-glycynhetinate.
  • Stearyl glycyrrhetinate is preferred.
  • compositions of the present invention may also contain a safe and effective amount of an anti-cellulite agent.
  • Suitable agents may include, xanthine compounds (e.g., caffeine, theophylline, theobromine, and aminophylline).
  • compositions of the present invention may also contain a safe and effective amount of a topical anesthetic.
  • topical anesthetic drugs include benzocaine, lidocaine, bupivacaine, chlorprocaine, dibucaine, etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine, procaine, cocaine, ketamine, pramoxine, phenol, and pharmaceutically acceptable salts thereof.
  • compositions of the present invention may contain a tanning compound.
  • the compositions can contain from about 0.1% to about 20%, or from about 2% to about 7%, or from about 3% to about 6%, by weight of the composition, of dihydroxyacetone as an artificial tanning compound.
  • Dihydroxyacetone which is also known as DHA or 1,3-dihydroxy-2-propanone, is a white to off-white, crystalline powder. This material can be represented by the chemical formula C 3 H 6 O 3 .
  • the compound can exist as a mixture of monomers and dimers, with the dimers predominating in the solid crystalline state. Upon heating or melting, the dimers break down to yield the monomers. This conversion of the dimeric form to the monomeric form also occurs in aqueous solution.
  • Dihydroxyacetone is also known to be more stable at acidic pH values. See The Merck Index, Tenth Edition, entry 3167, p. 463 (1983 ), and " Dihydroxyacetone for Cosmetics", E. Merck Technical Bulletin, 03-304 110, 319 897, 180 588 .
  • compositions of the present invention may contain a skin-lightening agent.
  • the compositions can contain from about 0.1 % to about 10%, or from about 0.2% to about 5%, or from about 0.5% to about 2%, by weight of the composition, of a skin lightening agent.
  • Suitable skin lightening agents include those known in the art, including kojic acid, arbutin, ascorbic acid and derivatives thereof (e.g., magnesium ascorbyl phosphate or sodium ascorbyl phosphate), and extracts (e.g., mulberry extract, placental extract).
  • Skin lightening agents suitable for use herein also include those described in the PCT publication No. 95/34280 , in the name of Hillebrand, corresponding to PCT Application No.
  • compositions of the present invention may comprise a skin soothing or skin-healing compound.
  • Skin soothing or skin healing compounds suitable for use herein include panthenoic acid derivatives (including panthenol, dexpanthenol, ethyl panthenol), aloe vera, allantoin, bisabolol, and dipotassium glycyrrhizinate.
  • a safe and effective amount of a skin soothing or skin healing compound may be added to the present composition, foe example, from about 0.1 % to about 30%, or from about 0.5% to about 20%, or from about 0.5% to about 10%, by weight of the composition formed.
  • compositions of the present invention may contain an anti-microbial or anti-fungal compound. Such compounds are capable of destroying microbes, preventing the development of microbes or preventing the pathogenic action of microbes.
  • a safe and effective amount of an anti-microbial or anti-fungal compound may be added to the present compositions, for example, from about 0.001% to about 10%, or from about 0.01% to about 5%, or from about 0.05% to about 2%.
  • antimicrobial and antifungal compounds examples include ⁇ -lactam drugs, quinolone drugs, ciprofloxacin, norfloxacin, tetracycline, erythromycin, amikacin, 2,4,4'-trichloro-2'-hydroxy diphenyl ether, 3,4,4'-trichlorobanilide, phenoxyethanol, phenoxy propanol, phenoxyisopropanol, doxycycline, capreomycin, chlorhexidine, chlortetracycline, oxytetracycline, clindamycin, ethambutol, hexamidine isethionate, metronidazole, pentamidine, gentamicin, kanamycin, lineomycin, methacycline, methenamine, minocycline, neomycin, netilmicin, paromomycin, streptomycin, tobramycin, miconazole, tetracycline hydrochloride, erythromycin
  • Examples of compounds useful herein include those selected from benzoyl peroxide, 3-hydroxy benzoic acid, glycolic acid, lactic acid, 4-hydroxy benzoic acid, 2-hydroxybutanoic acid, 2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, cis-retinoic acid, trans-retinoic acid, retinol, phytic acid, N-acetyl-L-cysteine, lipoic acid, azelaic acid, arachidonic acid, benzoylperoxide, tetracycline, ibuprofen, naproxen, hydrocortisone, acetominophen, resorcinol, phenoxyethanol, phenoxypropanol, phenoxyisopropanol, 2,4,4'-trichloro-2'-hydroxy diphenyl ether, 3,4,4'-trichlorocarbanilide, octopirox, lidocaine hydrochloride, clotrimazole, miconazo
  • compositions of the subject invention may optionally contain a sunscreen compound.
  • sunscreen compound includes both sunscreen agents and physical sun blocks. Suitable sunscreen compounds may be organic or inorganic.
  • Inorganic sunscreens useful herein include the following metallic oxides; titanium dioxide having an average primary particle size of from about 15 nm to about 100 nm, zinc oxide having an average primary particle size of from about 15 nm to about 150 nm, zirconium oxide having an average primary particle size of from about 15 nm to about 150 nm, iron oxide having an average primary particle size of from about 15 nm to about 500 nm, and mixtures thereof.
  • the inorganic sunscreens can be present in the amount of from about 0.1 % to about 20%, or from about 0.5% to about 10%, or from about 1% to about 5%, by weight of the composition.
  • sunscreen compounds include, for example: p-aminobenzoic acid, its salts and its derivatives (ethyl, isobutyl, glyceryl esters; p-dimethylaminobenzoic acid); anthranilates (i.e., o-aminobenzoates; methyl, menthyl, phenyl, benzyl, phenylethyl, linalyl, terpinyl, and cyclohexenyl esters); salicylate esters (amyl, phenyl, octyl, benzyl, menthyl, glyceryl, and di-pro-pyleneglycol esters); cinnamic acid derivatives (menthyl and benz
  • Desirable compounds include 2-ethylhexyl-p-methoxycinnamate (commercially available as PARSOL MCX), 4,4'-t-butyl methoxydibenzoyl-methane (commercially available as PARSOL 1789), 2-hydroxy-4-methoxybenzophenone, octyldimethyl-p-aminobenzoic acid, digalloyltrioleate, 2,2-dihydroxy-4-methoxybenzophenone, ethyl-4-(bis(hydroxy-propyl))aminobenzoate, 2-ethylhexyl-2-cyano-3,3-diphenylacrylate, 2-ethylhexyl-salicylate, glyceryl-p-aminobenzoate, 3,3,5-tri-methylcyclohexylsalicylate, methylanthranilate, p-dimethyl-aminobenzoic acid or aminobenzoate, 2-ethy
  • the organic sunscreen compounds used in the compositions of the invention are 2-ethylhexyl-p-methoxycinnamate, butylmethoxydibenzoyl-methane, 2-hydroxy-4-methoxybenzo-phenone, 2-phenylbenzimidazole-5-sulfonic acid, octyldimethyl-p-aminobenzoic acid, octocrylene and mixtures thereof.
  • Useful sunscreen compounds are also described in U.S. Patent 4,937,370 issued to Sabatelli on Jun. 26, 1990 , and U.S. Patent 4,999,186 issued to Sabatelli & Spirnak on Mar. 12, 1991 .
  • the sun-screening agents disclosed therein have, in a single molecule, two distinct chromophore moieties that exhibit different ultra-violet radiation absorption spectra.
  • One of the chromophore moieties absorbs predominantly in the UVB radiation range and the other absorbs strongly in the UVA radiation range.
  • Desirable members of this class of sun-screening agents are 4-N,N-(2-ethylhexyl)methyl-aminobenzoic acid ester of 2,4-dihydroxybenzophenone; N,N-di-(2-ethylhexyl)-4-arninobenzoic acid ester with 4-hydroxydibenzoylmethane; 4-N,N-(2-ethylhexyl)methyl-aminobenzoic acid ester with 4-hydroxydibenzoyhnethane; 4-N,N-(2-ethylhexyl)methyl-aminobenzoic acid ester of 2-hydroxy-4-(2-hydroxyethoxy) benzophenone; 4-N,N-(2-ethylhexyl)-methylaminobenzoic acid ester of 4-(2-hydroxyetboxy)dibenzoylmethane; N,N-di-(2-ethylhexyl)-4-aminobenzoic acid ester
  • sunscreen compounds include 4,4'-t-butylmethoxydibenzoyl-methane, 2-ethylhexyl-p-methoxycinnamate, phenyl benzimidazole sulfonic acid, and octocrylene.
  • a safe and effective amount of the organic sunscreen compound is used, typically from about 1% to about 20%, more typically from about 2% to about 10% by weight of the composition. Exact amounts will vary depending upon the sunscreen or sunscreens chosen and the desired Sun Protection Factor (SPF).
  • SPF Sun Protection Factor
  • compositions of the invention may contain a particulate material, for example, a metallic oxide. These particulates can be coated or uncoated, charged or uncharged. Charged particulate materials are disclosed in U.S. Patent 5,997,887, to Ha, et al.
  • Particulate materials useful herein include; bismuth oxychloride, iron oxide, mica, mica treated with barium sulfate and TiO 2 , silica, nylon, polyethylene, talc, styrene, polypropylene, ethylene/acrylic acid copolymer, sericite, titanium dioxide, bismuth oxychloride, iron oxide, aluminum oxide, silicone resin, barium sulfate, calcium carbonate, cellulose acetate, polymethyl methacrylate, and mixtures thereof.
  • Inorganic particulate materials e.g., TiO 2 , ZnO, or ZrO 2 are commercially available from a number of sources.
  • a suitable particulate material contains the material available from U.S. Cosmetics (TRONOX TiO 2 series, SAT-T CR837, a rutile TiO 2 ).
  • Particulate materials can be present in the composition in levels of from about 0.01 % to about 2%, or from about 0.05% to about 1.5%, or from about 0.1 % to about 1 %, by weight of the composition.
  • compositions of the present invention may contain a conditioning agent selected from humectants, moisturizers, or skin conditioners.
  • a conditioning agent selected from humectants, moisturizers, or skin conditioners.
  • these materials can be employed and each can be present at a level of from about 0.01% to about 20%, more preferably from about 0.1 % to about 10%, and still more preferably from about 0.5% to about 7% by weight of the composition.
  • These materials include, guanidine; urea; glycolic acid and glycolate salts (e.g.
  • aloe vera in any of its variety of forms (e.g., aloe vera gel); polyhydroxy alcohols such as sorbitol, mannitol, xylitol, erythritol, glycerol, hexanetriol, butanetriol, propylene glycol, butylene glycol, hexylene glycol and the like; polyethylene glycols; sugars (e.g., melibiose) and starches; sugar and starch derivatives (e.g., alkoxylated glucose, fucose, glucosamine); hyaluronic acid; lactamide monoethanolamine; acetamide monoethanolamine; panthenol; allantoin; and mixtures thereof. Also useful herein are the propoxylated glycerols described in
  • esters are derived from a sugar or polyol moiety and one or more carboxylic acid moieties.
  • ester materials are further described in, U.S. Patent 2,831,854 ; U.S. Patent 4,005,196, to Jandacek, issued Jan. 25, 1977 ; U.S. Patent 4,005,195, to Jandacek, issued Jan. 25, 1977 ; U.S. Patent 5,306,516, to Letton et al, issued Apr. 26, 1994 ; U.S. Patent 5,306,515, to Letton et al, issued Apr. 26, 1994 ; U.S. Patent 5,305,514, to Letton et al, issued Apr.
  • Desirable conditioning agents are selected from urea, guanidine, sucrose polyester, panthenol, dexpanthenol, allantoin, and combinations thereof.
  • compositions of the present invention can contain one or more thickening agents, can be from about 0.1 % to about 5%, or from about 0.1 % to about 4%, or from about 0.25% to about 3%, by weight of the composition.
  • thickening agents include those selected from the following:
  • polymers are crosslinked compounds containing one or more monomers derived from acrylic acid, substituted acrylic acids, and salts and esters of these acrylic acids and the substituted acrylic acids, wherein the crosslinking agent contains two or more carbon-carbon double bonds and is derived from a polyhydric alcohol.
  • Polymers useful in the present invention are more fully described in U.S. Patent 5,087,445, to Haffey et al, issued Feb. 11, 1992 ; U.S. Patent 4,509,949, to Huang et al, issued Apr. 5,1985 ; U.S. Patent 2,798,053, to Brown, issued Jul. 2, 1957 ; and in CTFA International Cosmetic Ingredient Dictionary, Fourth Edition, 1991, pp. 12 and 80 .
  • carboxylic acid polymers useful herein include the carbomers, which are homopolymers of acrylic acid crosslinked with allyl ethers of sucrose or pentaerytritol.
  • the carbomers are available as the CarbopolTM 900 series from B.F. Goodrich (e.g., CarbopolTM 954).
  • carboxylic acid polymeric agents include copolymers of C 10-30 alkyl acrylates with one or more monomers of acrylic acid, methacrylic acid, or one of their short chain (i.e., C 1-4 alcohol) esters, wherein the crosslinking agent is an allyl ether of sucrose or pentaerytritol.
  • copolymers are known as acrylates/ C 10-30 alkyl acrylate crosspolymers and are commercially available as CarbopolTM 1342, CarbopolTM 1382, Pemulen TR-1, and Pemulen TR-2, from B.F. Goodrich.
  • carboxylic acid polymer thickeners useful herein are those selected from carbomers, acrylates/C 10 -C 30 alkyl acrylate crosspolymers, and mixtures thereof.
  • compositions of the present invention can optionally contain crosslinked polyacrylate polymers useful as thickeners or gelling agents including both cationic and nonionic polymers, with the cationics being generally preferred.
  • useful crosslinked nonionic polyacrylate polymers and crosslinked cationic polyacrylate polymers are those described in U.S. Patent 5,100,660, to Hawe et al, issued Mar. 31, 1992 ; U.S. Patent 4,849,484 , to Heard, issued Jul. 18; 1989; U.S. Patent 4,835,206, to Farrar et al, issued May 30, 1989 ; U.S. Patent 4,628,078 to Glover et al issued Dec. 9, 1986 ; U.S. Patent 4,599,379 to Flesher et al issued Jul. 8, 1986 ; and EP 228,868, to Farrar et al, published Jul. 15, 1987 .
  • compositions of the present invention can optionally contain polyacrylamide polymers, especially nonionic polyacrylamide polymers including substituted branched or unbranched polymers. More preferred among these polyacrylamide polymers is the nonionic polymer given the CTFA designation polyacrylamide and isoparaffin and laureth-7, available under the Trade name Sepigel 305 from Seppic Corporation (Fairfield, N.J.).
  • polyacrylamide polymers useful herein include multi-block copolymers of acrylamides and substituted acrylamides with acrylic acids and substituted acrylic acids.
  • Commercially available examples of these multi-block copolymers include Hypan SR150H, SS500V, SS500W, SSSA100H, from Lipo Chemicals, Inc., (Patterson, N.J.).
  • Polysaccharides refer to gelling agents that contain a backbone of repeating sugar (i.e., carbohydrate) units.
  • Nonlimiting examples of polysaccharide gelling agents include those selected from cellulose, carboxymethyl hydroxyethylcellulose, cellulose acetate propionate carboxylate, hydroxyethylcellulose, hydroxyethyl ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, methyl hydroxyethylcellulose, microcrystalline cellulose, sodium cellulose sulfate, and mixtures thereof.
  • alkyl-substituted celluloses are also useful herein.
  • the hydroxy groups of the cellulose polymer is hydroxyalkylated (preferably hydroxyethylated or hydroxypropylated) to form a hydroxyalkylated cellulose that is then further modified with a C 10 -C 30 straight chain or branched chain alkyl group through an ether linkage.
  • these polymers are ethers of C 10 -C 30 straight or branched chain alcohols with hydroxyalkylcelluloses.
  • alkyl groups useful herein include those selected from stearyl, isostearyl, lauryl, myristyl, cetyl, isocetyl, cocoyl (i.e.
  • alkyl groups derived from the alcohols of coconut oil palmityl, oleyl, linoleyl, linolenyl, ricinoleyl, behenyl, and mixtures thereof.
  • Preferred among the alkyl hydroxyalkyl cellulose ethers is the material given the CTFA designation cetyl hydroxyethylcellulose, which is the ether of cetyl alcohol and hydroxyethylcellulose. This material is sold under the trade name NatrosolTM CS Plus from Aqualon Corporation (Wilinington, Del.).
  • polysaccharides include scleroglucans that are a linear chain of (1-3) linked glucose units with a (1-6) linked glucose every three units, a commercially available example of which is ClearogelTM CS11 from Michel Mercier Products Inc. (Mountainside, N.J.).
  • thickening and gelling agents useful herein include materials that are primarily derived from natural sources.
  • Nonlimiting examples of these gelling agent gums include acacia, agar, algin, alginic acid, ammonium alginate, amylopectin, calcium alginate, calcium carrageenan, carnitine, carrageenan, dextrin, gelatin, gellan gum, guar gum, guar hydroxypropyltrimonium chloride, hectorite, hyaluroinic acid, hydrated silica, hydroxypropyl chitosan, hydroxypropyl guar, karaya gum, kelp, locust bean gum, natto gum, potassium alginate, potassium carrageenan, propylene glycol alginate, sclerotium gum, sodium carboyxmethyl dextran, sodium carrageenan, tragacanth gum, xanthan gum, and mixtures thereof.
  • compositions of the invention can therefore include desirable thickening agents such as carboxylic acid polymers, crosslinked polyacrylate polymers, polyacrylamide polymers, and mixtures thereof, more preferably selected from carboxylic acid polymers, polyacrylamide polymers, and mixtures thereof.
  • desirable thickening agents such as carboxylic acid polymers, crosslinked polyacrylate polymers, polyacrylamide polymers, and mixtures thereof, more preferably selected from carboxylic acid polymers, polyacrylamide polymers, and mixtures thereof.
  • compositions useful for the uses of the present invention are generally prepared by conventional methods such as are known in the art of making topical compositions. Such methods typically involve mixing of the ingredients in one or more steps to a relatively uniform state, with or without heating, cooling, application of vacuum, and the like.
  • compositions of the present invention are useful for use in promoting wound closure, stimulating cellular growth, stimulating collagen production and/or stimulating fibronectin production in skin tissues. Such increased cell growth and/or increased collagen or fibronectin production can help regulate or rejuvenate mammalian skin tissues.
  • the compositions of the invention can be used for both prophylactic and therapeutic treatment of skin conditions.
  • compositions of the invention can be used for wound healing, thickening skin tissue (i.e., building the epidermis and/or dermis layers of the skin and where applicable the keratinous layers of the nail and hair shaft), preventing and/or retarding atrophy of mammalian skin, preventing and/or retarding the appearance of spider vessels and/or red blotchiness on mammalian skin, preventing and/or retarding the appearance of dark circles under the eye of a mammal, preventing and/or retarding sallow-colored mammalian skin, preventing and/or retarding sagging of mammalian skin, softening and/or smoothing lips, hair and nails of a mammal, preventing and/or relieving itch of mammalian skin, regulating skin texture (e.g. wrinkles and fine lines), and improving skin color (e.g. redness, freckles).
  • thickening skin tissue i.e., building the epidermis and/or dermis layers of the skin and where
  • Treating skin tissues involves topically applying to the skin tissue a safe and effective amount of a composition of the present invention.
  • the amount of the composition that is applied, the frequency of application and the period of use will vary widely depending upon the level of the acetylsalicylic acid, gibberellic acid, jasmonic acid, salicylic acid, or zeatin in a given composition and the level of regulation desired, for example, in light of the level of skin tissue damage present or expected to occur.
  • the composition is chronically applied to the skin.
  • chromenic topical application is meant continued topical application of the composition over an extended period during the subject's lifetime, for example, for a period of at least about one week, or for a period of at least about one month, or for at least about three months, or for at least about six months, or for at least about one year. While benefits are obtainable after various periods of use (e.g., two, five, ten or twenty days), chronic application can continue throughout the subject's lifetime. Typically applications would be on the order of about once per day over such extended periods, however application rates can vary from about once per week up to about three times per day or more.
  • compositions of the present invention can be employed to provide a skin appearance and/or feel benefit.
  • Quantities of the present compositions that are typically applied per application are, in mg composition/cm 2 skin, from about 0.01 mg/cm 2 to about 10 mg/cm 2 .
  • a desirable and useful application amount is about 1 mg/cm 2 to about 2 mg/cm 2 .
  • Regulating skin tissue condition can be practiced by applying a composition in the form of a skin lotion, cream, gel, foam, ointment, paste, emulsion, spray, conditioner, tonic, cosmetic, lipstick, foundation, nail polish, after-shave, or the like that is preferably intended to be left on the skin or other keratin structure for some esthetic, prophylactic, therapeutic or other benefit (i.e., a "leave-on" composition).
  • a composition in the form of a skin lotion, cream, gel, foam, ointment, paste, emulsion, spray, conditioner, tonic, cosmetic, lipstick, foundation, nail polish, after-shave, or the like that is preferably intended to be left on the skin or other keratin structure for some esthetic, prophylactic, therapeutic or other benefit (i.e., a "leave-on" composition).
  • the composition After applying the composition to the skin, it can be left on the skin for a period of at least about 15 minutes,
  • any part of the external portion of the face, hair, and/or nails can be treated, e.g., face, lips, gums, under-eye area, eyelids, scalp, neck, torso, arms, hands, legs, feet, fingernails, toenails, scalp hair, eyelashes, eyebrows, etc.
  • the composition can be applied with the fingers or with an implement or device (e.g., pad, cotton ball, applicatorpen, spray applicator, dental applicator and the like).
  • Another approach to ensure a continuous exposure of the skin to at least a minimum level of the beneficial compositions of the invention is to apply the composition in a patch, for example, to selected tissues such as the face.
  • a patch for example, to selected tissues such as the face.
  • the patch can be occlusive, semi-occlusive or non-occlusive and can be adhesive or non-adhesive.
  • the composition can be contained within the patch or be applied to the skin prior to application of the patch.
  • the patch can also include additional compounds such as chemical initiators for exothermic reactions such as those described in U.S. Patent Nos.
  • the patch is preferably left on the skin for a period of at least about 5 minutes, or at least about 15 minutes, or at least about 30 minutes, or at least about 1 hour, or at night as a form of night therapy.
  • This Example provides data showing the cell proliferating effect of acetylsalicylic acid and salicylic acid on human skin fibroblasts.
  • a human skin fibroblast cell line (Clonetics, Walkersville, MD, normal human dermal fibroblasts, neonatal) was tested to ascertain whether exposure to acetylsalicylic acid and salicylic acid of the invention would stimulate cellular proliferation.
  • the proliferative response of the human skin fibroblast cell line to acetylsalicylic acid and salicylic acid was measured in a 96-well assay system using serum-free medium as a control. Both compounds were tested at three concentrations, 1x10 -4 M, 1x10 -5 M and 1x10 -6 M.
  • DMEM Dulbecco's Modified Eagle's Medium
  • FBS fetal bovine serum
  • the final rinse was aspirated and 100 ⁇ l of the 1 x 10 -4 M; 1 x 10 -5 M or 1 x 10 -6 M solutions of acetylsalicylic acid and salicylic acid each were added to 5 wells.
  • 100 ⁇ l of vehicle (serum-free DMEM) was added to 5 wells as control. All wells were incubated for 28 hours at 37°C in a humidified, 5% CO 2 atmosphere. After incubation, 20 ⁇ l of Cell Titer 96 Aqueous One Solution (Promega, Madison, WI) was added to all wells. The plate was swirled gently and placed back in the incubator for 45 minutes and spectrophotometric absorbance was read at 490 nm.
  • Table 1 and Figure 1 illustrate the cell proliferating effect of acetylsalicylic acid on human skin fibroblasts, where the concentration of acetylsalicylic acid varied between 1 x 10 -4 M (designated ASA4), 1 x 10 -5 M (designated ASA5) and 1 x 10 -6 M (designated ASA6).
  • Table 1 Effect of Acetylsalicylic acid on Cell Proliferation Group Number of Points Mean Standard Deviation Standard Error of Mean Median Control 5 0.3784 0.009317 0.004167 0.3800 ASA4 5 0.5406 0.03051 0.01364 0.5290 ASA5 5 0.6276 0.03310 0.01480 0.6270 ASA6 5 0.6590 0.04973 0.02224 0.6590
  • the data provided in Table 1 and Figure 1 indicate that acetylsalicylic acid has strong cell proliferating activity at all concentrations (P ⁇ 0.001 at all concentrations). The effect on cell proliferation was dose dependent, with a greater effect at lower, rather than higher, concentrations.
  • Table 2 and Figure 2 illustrate the cell proliferating effect of salicylic acid on human skin fibroblasts, where the concentration of salicylic acid varied between 1 x 10 -4 M (designated SA4), 1 x 10 -5 M (designated SA5) and 1 x 10 -6 M (designated SA6).
  • Table 2 Effect of Salicylic acid on Cell Proliferation Group Number of Points Mean Standard Deviation Standard Error of Mean Median Control 5 0.3368 0.01201 0.005370 0.3310 SA4 5 0.3916 0.03116 0.01393 0.4050 SA5 5 0.5004 0.02532 0.01133 0.5110 SA6 5 0.4668 0.01599 0.007151 0.4690
  • the data provided in Table 2 and Figure 2 indicates that salicylic acid has strong cell proliferating activity especially at the lower concentrations (P ⁇ 0.001 at concentrations of 10 -5 and 10 -6 M). The effect on cell proliferation was dose dependent manner with a greater effect at lower, rather than higher, concentrations.
  • This Example provides data showing the cell proliferating effect of jasmonic acid, zeatin and gibberellic acid on human skin keratinocytes.
  • a human skin keratinocyte cell line from Clonetics (Walkersville, MD, normal human epidermal keratinocytes, neonatal, catalog number cc-2503) was exposed to the jasmonic acid, zeatin and gibberellic acid (from Sigma Chemical Co.) to determine their effect on proliferation of keratinocytes.
  • the gibberellic acid used had the following structure (Gibberellin A 3 ).
  • the proliferative response of these human skin keratinocytes to the test compounds was measured in a 96-well assay system using keratinocyte basal medium (KBM, Clonetics, catalog number CC-3103) as a control All compounds were tested at three concentrations, 1x10 -4 M, 1x10 -5 M and 1x10 -6 M.
  • Cells were seeded into a 96 well plate at a concentration of 2x10 3 cells in 100 ⁇ l of KBM. The plate was incubated for 24 hours at 37° C in a humidified 5% CO 2 atmosphere.
  • Table 3 and Figure 3 illustrate the cell proliferating effect of jasmonic acid on human keratinocytes, where the concentration of jasmonic acid varied between 1x10 -4 M (designated JA4), 1 x 10 -5 M (designated JA5) and 1 x 10 -6 M (designated JA6).
  • Table 3 Effect of Jasmonic Acid on Cell Proliferation Group Number of Points Mean Standard Deviation Standard Error of Mean Median A9 5 0.5732 0.02720 0.01216 0.5860 JA5 5 0.7628 0.03805 0.01702 0.7750 JA6 5 0.7734 0.06328 0.02830 0.7970 Control 5 0.5094 0.07334 0.03280 0.5050
  • the data provided in Table 3 and Figure 3 indicates that jasmonic acid has strong cell proliferating activity especially at the lower concentrations (P ⁇ 0.001 at concentrations of 10 -5 and 10 -6 M). The effect on cell proliferation was greater at lower, rather than higher, concentrations.
  • Table 4 and Figure 4 illustrate the cell proliferating effect of t-zeatin on human keratinocytes, where the concentration of t-zeatin varied between 1 x 10 -4 M (designated ZA4), 1 x 10 -5 M (designated ZA5) and 1 x 10 -6 M (designated ZA6).
  • Table 4 Effect of t-Zeatin on Cell Proliferation Group Number of Points Mean Standard Deviation Standard Error of Mean Median ZA4 5 0.7726 0.03785 0.01693 0.7880 ZA5 5 0.8716 0.03179 0.01421 0.8790 ZA6 5 0.9770 0.05141 0.02299 0.9830 Control 5 0.5336 0.07444 0.03329 0.5650
  • the data provided in Table 4 and Figure 4 indicate that t-zeatin has strong cell proliferating activity at all concentrations (P ⁇ 0.001 at all concentrations). The effect on cell proliferation was dose dependent manner with a greater effect at lower, rather than higher, concentrations.
  • Table 5 and Figure 5 illustrate the cell proliferating effect of gibberellic acid on human keratinocytes, where the concentration of gibberellic acid varied between 1 x 10 -4 M (designated GA4), 1 x 10 -5 M (designated GA5) and 1 x 10 -6 M (designated GA6).
  • Table 5 Effect of Gibberellic acid on Cell Proliferation Group Number of Points Mean Standard Deviation Standard Error of Mean Median GA4 5 0.6512 0.01256 0.005616 0.6510 GA5 5 0.8184 0.04813 0.02152 0.8210 GA6 5 0.7854 0.04743 0.02121 0.7900 Control 5 0.5308 0.06833 0.03056 0.5220
  • the data provided in Table 5 and Figure 5 indicate that giberrellic acid has strong cell proliferating activity at all concentrations (P ⁇ 0.001 at all concentrations). The effect on cell proliferation was greater at lower, rather than higher, concentrations.
  • This example provides data showing that jasmonic acid, zeatin and gibberellic acid stimulate collagen production.
  • the stimulation response of jasmonic acid, zeatin and gibberellic acid (Gibberellin A 3 , formula V) on collagen production in the human skin fibroblast cell line was measured using Takara Biomedicals EIA assay kit (TAK MK101) sold by Panvera (Madison, WI).
  • TAK MK101 Takara Biomedicals EIA assay kit sold by Panvera (Madison, WI).
  • the cells were first grown in a 96-well assay system using Dulbecco's Modified Eagle's Medium (DMEM) with 10% fetal bovine serum (FBS) both purchased from Sigma Chemical Co, St. Louis, MO. Serum-free DMEM was used as a control.
  • DMEM Dulbecco's Modified Eagle's Medium
  • FBS fetal bovine serum
  • All compounds were tested at three concentrations 1x10 -4 M, 1x10 -5 M and 1x10 -6 M.
  • Cells were seeded into a 96 well plate at a concentration of 5 x 10 3 cells in 100 ⁇ l of DMEM containing 10% fetal bovine serum (FBS, Sigma Chemical Co., St. Louis, MO). Plate was incubated for 24 hours at 37° C in a humidified 5% CO 2 atmosphere. After incubation, the medium was aspirated and the wells were rinsed twice with 100 ⁇ l of serum-free DMEM.
  • FBS fetal bovine serum
  • 100 ⁇ l of vehicle (serum-free DMEM) was added to 4 wells as control. The plate was incubated for 48 hours at 37°C in a humidified, 5% CO 2 atmosphere.
  • the assay was done by using the recommended 20ul of the supernatant from each well of the 96-well plate. Standard buffer and stop solutions were freshly prepared before running the assay. 100ul of antibody-POD conjugate solution (supplied with the kit) was added into the wells using pre antibody coated 96 well plate (supplied with the kit). 20ul of standard and test solutions (from the other 96-well plate containing fibroblasts) were added to appropriate wells. Plate was mixed gently, sealed and incubated for three hrs. at 37°C.
  • substrate solution hydrogen peroxide and tetramethylbenzidine in a buffer solution, supplied with the kit
  • stop solution freshly prepared 1N H 2 SO 4
  • Table 6 and Figure 6 illustrate the collagen production of human fibroblast cells exposed to varying concentrations of jasmonic acid, gibberellic acid or t-zeatin.
  • the concentration of jasmonic acid varied between 1x10 -4 M (designated JA4), 1 x 10 -5 M (designated JA5) and 1x10 -6 M (designated JA6):
  • the concentration of gibberellic acid varied between 1x 10 -4 M (designated GA4), 1 x 10 -5 M (designated GAS) and 1 x 10 -6 M , (designated GA6).
  • the concentration of zeatin varied between 1x 10 -4 M (designated ZA4), 1 x 10 -5 M (designated ZA5) and 1 x 10 -6 M (designated ZA6).
  • Table 6 Effect of Jasmonic Acid, Gibberellic Acid and Zeatin on Collagen Production by Human Fibroblasts Group Number of Points Mean Standard Deviation Standard Error of Mean Median JA4 2 0.8040 0.009899 0.007000 0.8040 JA5 2 0.7895 0.006364 0.004500 0.7895 JA6 2 0.7475 0.007778 0.005500 0.7475 GA4 2 0.7780 0.01838 0.01300 0.7780 GA5 2 0.8365 0.04172 0.02950 0.8365 GA6 2 0.8630 0.008485 0.006000 0.8630 A4 2 0.7665 0.02758 0.01950 0.7665 ZA5 2 0.8115 0.0007071 0.0005000 0.8115 ZA6 2 0.7715 0.006364 0.004500 0.7715 CNA5 4 0.7483 0.006238 0.003119 0.7495 Control 4 0.7388 0.01431 0.007157 0.7330
  • the data provided in Table 6 and Figure 6 indicate that jasmonic acid, gibe
  • This example provides data showing the effect of jasmonic acid, gibberellic acid and zeatin on fibronectin production.
  • the stimulation response of jasmonic acid, gibberellic acid (Gibberellin A 3 , formula V) and zeatin on fibronectin production in the human skin fibroblast cell line was measured using Takara Biomedicals EIA assay kit (TAK MK115) sold by Panvera (Madison, WI).
  • the cells were first grown in a 96-well assay system using Dulbecco's Modified Eagle's Medium (DMEM) with 10% fetal bovine serum (FBS) both purchased from Sigma Chemical Co, St. Louis, MO. Serum-free DMEM was used as a control.
  • DMEM Dulbecco's Modified Eagle's Medium
  • FBS fetal bovine serum
  • the compounds were tested in three concentrations 1x10 -4 M, 1x10 -5 M and 1x10 -6 M in duplicate.
  • Cells were seeded into a 96 well plate at a concentration of 1x10 4 cells in 100 ⁇ l of DMEM containing 10% fetal bovine serum (FBS, Sigma Chemical Co., St. Louis, MO). The plate was incubated for 48 hours at 37° C in a humidified 5% CO 2 atmosphere. After incubation, the medium was aspirated and the wells were rinsed twice with 100 ⁇ l of serum-free DMEM.
  • FBS fetal bovine serum
  • 100 ⁇ l of vehicle (serum-free DMEM) was added to 2 wells as control. The plate was incubated for 48 hours at 37°C in a humidified, 5% CO 2 atmosphere.
  • the fibronectin assay was performed using the recommended 100 ⁇ l of the supernatant from each well of the 96-well plate. Standard buffer and stop solutions were freshly prepared before running the assay. A pre-antibody-coated 96 well plate (provided with the kit) was used to transfer the test samples and control. The plate was mixed, sealed and incubated for 1 hour at 37 °C. All the wells were washed after removing sample solution, 3 times (300 ⁇ l) with washing buffer. 100ul of antibody-POD conjugate solution was added into the wells. Plate was mixed, sealed and incubated for one hour at 37 °C. Solutions were removed and the wells were washed 3 times with washing buffer. All the wells were completely emptied at the end of washing from any liquid.
  • substrate solution hydrogen peroxide and tetramethylbenzidine in a buffered solution
  • stop solution freshly prepared 1N H 2 SO 4
  • Table 7 and Figure 7 illustrate the fibronectin production of human fibroblast cells exposed to varying concentrations of jasmonic acid, gibberellic acid or t-zeatin.
  • Table 7 Summary of Data Group Number of Points Mean Standard Deviation Standard Error of Mean Median JA4 2 0.2060 0.002828 0.002000 0.2060 JA5 2 0.2025 0.0007071 0.0005000 0.2025 JA6 2 0.1955 0.0007071 0.0005000 0.1955 GA4 2 0.2150 0.005657 0.004000 0.2150 GA5 2 0.2090 0.004243 0.003000 0.2090 GA6 2 0.2225 0.002121 0.001500 0.2225 ZA4 2 0.2075 0.009192 0.006500 0.2075 ZA5 2 0.2110 0.007071 0.005000 0.2110 ZA6 2 0.1995 0.002121 0.001500 0.1995 Control 2 0.1660 0.004243 0.003000 0.1660
  • the concentration of jasmonic acid varied between 1 x 10 -4 M (designated JA4), 1 x 10 -5 M (designated JA5) and 1 x 10 -6 M (designated JA6).
  • the concentration of gibberellic acid varied between 1 x 10 -4 M (designated GA4), 1 x 10 -5 M (designated GA5) and 1 x 10 -6 M (designated GA6).
  • the concentration of zeatin varied between 1 x 10 -4 M (designated ZA4), 1 x 10 -5 M (designated ZA5) and 1 x 10 -6 M (designated ZA6).
  • the example provides data showing the wound healing effect of jasmonic acid, gibberellic acid and zeatin in an animal model.
  • the skin was first tented and the punch was driven through the tented skin to generate both wounds with a single stroke.
  • the upper left quadrant wound site of the animal was assigned to receive the control solution (WFI).
  • the lower left quadrant wound site received gibberellic acid.
  • the upper right quadrant wound site received zeatin and the lower right wound site received jasmonic acid.
  • the wound sites were dosed 5 times (twice on Day 0, Day 1, and once on Day 2). All wounds were treated with 5 ⁇ l of test or control solutions. Wounds were allowed to absorb the solutions for 5 minutes before returning the animals to their cages for recovery. All the animals were housed singly. The in-life phase for the animals is 5 days.
  • Figure 8 illustrates the effects of jasmonic acid, gibberellic acid and zeatin on wound closure.
  • jasmonic acid significantly accelerated the rate of wound healing in comparison to the other compounds and to the control. This effect is most significant on day 1 but was also clearly evident on day 2 and day 3.
  • Control-treated wounds required over 2.5 days to close to the same extent achieved in jasmonic acid-treated wounds of the same wound size on day 1.
  • the rate of closure for all wounds decreased from day 2 to day 5, this trend toward accelerated healing by jasmonic acid continued throughout the test period.
  • Gibberellic acid also accelerated wound healing during the 24 to 48 hrs following treatment. Although this effect is not quite so prominent as the effect exhibited by jasmonic acid, gibberellic acid still encouraged wound closure to a greater extent than zeatin or than the control.
  • the example provides data showing that the rate of skin renewal is increased by compositions containing jasmonic acid or gibberellic acid in healthy female volunteers.
  • the stratum corneum renewal time is the time taken for the whole thickness of the stratum corneum to be exfoliated and replaced by new cells from the dividing epidermis. This renewal time is a fundamental indicator of skin health. Previous work has demonstrated that the turnover time of the stratum corneum can be measured non-intrusively by impregnating the skin with a fluorescent marker dye that binds avidly to the nonviable epidermal cells.
  • a dansyl chloride cell renewal study was conducted in healthy female volunteers ranging from 43-64 years of age. The study consisted of a two-week treatment period during which time the products were applied topically twice daily, including on weekend days, to the test sites. The area of application was designated, approximately 5cm x 10cm on the upper inner arm. The other arm served as a control with no product application. Two compounds, jasmonic acid (JA) and gibberellic acid (GA, Gibberellin A 3 , formula V) were separately tested at a concentration of 0.25% in hyaluronic acid (0.5% aqueous solution Eight females received jasmonic acid and seven females received gibberellic acid.
  • jasmonic acid JA
  • gibberellic acid Gibberellin A 3 , formula V
  • alpha hydroxy acids e.g. glycolic acid
  • the compositions of the invention may satisfy an ongoing need for skin cell renewal anti-aging compositions that do not cause unwanted side effects and that are gentle to the skin.

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Claims (40)

  1. Eine Zusammensetzung, die geeignet ist zur Verwendung in der Behandlung der Dermis, welche umfasst:
    einen dermatologisch verträglichen Trägerstoff;
    eine wirksame Menge einer Salicylatverbindung; und
    eine wirksame Menge einer Jasmonsäureverbindung, einer Gibberellinsäureverbindung und einer Zeatinverbindung.
  2. Die Zusammensetzung gemäß Anspruch 1, wobei die Zusammensetzung die Fibronektinproduktion in Säugetierfibroblasten stimulieren kann.
  3. Die Zusammensetzung gemäß Anspruch 1, wobei die Zusammensetzung Wundverschluss stimulieren kann.
  4. Die Zusammensetzung gemäß Anspruch 1, wobei die Gibberellinsäureverbindung eine Verbindung gemäß einer der Formeln III, IV, V, Va oder Vb ist:
    Figure imgb0044
    Figure imgb0045
    Figure imgb0046
    Figure imgb0047
    Figure imgb0048
  5. Die Zusammensetzung gemäß Anspruch 1, wobei die Jasmonsäureverbindung eine Verbindung gemäß einer der Formeln VI-IX ist:
    Figure imgb0049
    Figure imgb0050
    Figure imgb0051
    Figure imgb0052
     wobei:
    R3 ist Alkyl;
    R4 ist COOR oder -(CH2) n-OX, wobei n eine ganze Zahl von 1 bis 20 ist; R ist H oder Alkyl; X ist H oder 1 bis 6 Zuckerreste; und Y ist H, Alkyl oder 1 bis 6 Zuckerreste.
  6. Die Zusammensetzung gemäß Anspruch 1, wobei die Jasmonsäureverbindung Jasmonsäure, Hydroxy-Jasmonsäure, Dihydro-Jasmonsäure oder Dihydrohydroxy-Jasmonsäure ist
  7. Die Zusammensetzung gemäß Anspruch 1, wobei die Zeatinverbindung eine Verbindung der Formel X ist:
    Figure imgb0053
     wobei:
    R5 ist H, 3-Hydroxymethyl-3-Methylallyl, Alkyl, -(CH2)n-CH3 oder OZ;
    Z ist H, 1 bis 6 Zuckerreste oder -(CH2) n-Furan;
    R6 ist H, 3-Hydroxymethyl-3-Methylallyl, Alkyl, -(CH2)n-CH3 oder OZ; und n ist eine ganze Zahl von 1 bis 20.
  8. Die Zusammensetzung gemäß Anspruch 1, wobei die Zeatinverbindung Zeatin ist.
  9. Die Zusammensetzung gemäß Anspruch 1, wobei die wirksame Menge an Jasmosäureverbindung, Gibberellinsäureverbindung oder Zeatinverbindung eine Konzentration von ungefähr 0,001 Mikromolar bis ungefähr 10 Millimolar ist.
  10. Die Zusammensetzung gemäß Anspruch 1, wobei die wirksame Menge an Jasmosäureverbindung, Gibberellinsäureverbindung oder Zeatinverbindung eine Konzentration von ungefähr 1 Mikromolar bis ungefähr 5 Millimolar ist.
  11. Die Zusammensetzung gemäß Anspruch 1, wobei die Salicylatverbindung eine Verbindung der Formel I ist:
    Figure imgb0054
     wobei:
    R1 ist COOR oder -(CH2)n-OX;
    R ist H oder Alkyl; n ist eine ganze Zahl zwischen ungefähr 1 bis ungefähr 20;
    X ist H oder 1 bis 6 Zuckerreste;
    R2 ist COOR, -(CH2)n-OX, OCO-Alkyl, OY; und
    Y ist H, ein Alkyl oder 1 bis 6 Zuckerreste.
  12. Die Zusammensetzung gemäß Anspruch 1, wobei die Salicylatverbindung Salicylsäure oder Acetylsalicylsäure ist.
  13. Die Zusammensetzung gemäß Anspruch 1, wobei die Zusammensetzung des Weiteren einen oder mehrere zusätzliche Inhaltsstoffe umfasst.
  14. Die Zusammensetzung gemäß Anspruch 13, wobei der zusätzliche Inhaltsstoff eine Desquamationsverbindung, eine Anti-Akne-Verbindung, eine Anti-Falten-Verbindung, eine Vitamin-B3-Verbindung, eine Vitamin-E-Verbindung, eine Retinoidverbindung, eine Hydroxysäureverbindung, eine Anti-Oxidant-Verbindung, ein Radikalfänger, ein Chelatbildner, eine Flavonoidverbindung, ein Entzündungshemmer, eine Anti-Cellulite-Mittel, ein topisches Anästhetikum, ein Bräunungsmittel, ein Hautaufhellungsmittel, ein Hautheilmittel, eine antimikrobielle Verbindung, eine antimykotische Verbindung, eine Sonnenschutzverbindung, ein teilchenförmiges Material, ein Feuchtigkeitsmittel oder ein Verdickungsmittel ist.
  15. Die Zusammensetzung gemäß Anspruch 14, wobei die Vitamin-E-Verbindung Tocopherol, Tocopherolacetat, ein Tocopherolester oder eine Mischung davon ist.
  16. Die Zusammensetzung gemäß Anspruch 14, wobei die Retinoidverbindung ein Retinol, Retinal, Retinylester, Retinylpropionat, Retinsäure, Retinylpalmitat oder eine Mischung davon ist.
  17. Die Zusammensetzung gemäß Anspruch 14, wobei das teilchenförmige Material Glimmer, mit Bariumsulfat und TiO2 behandelter Glimmer, Kieselerde, Nylon, Polyethylen, Talk, Styren, Polypropylen, Ethylen/Acrylsäure-Copolymer, Serizit, Aluminiumoxid, Silikonharz, Bariumsulfat, Titaniumdioxid, Eisenoxid, Wismuthoxychlorid, Kalziumkarbonat, Zelluloseacetat, Polymethyl-Methacrylat oder ein Mischung davon ist.
  18. Die Zusammensetzung gemäß Anspruch 14, wobei die Sonnenschutzverbindung ein Metalloxid ist ausgewählt aus der Gruppe bestehend aus Titaniumdioxid mit einer durchschnittlichen primären Partikelgröße von ungefähr 15 nm bis ungefähr 100 nm, Zinkoxid mit einer durchschnittlichen primären Partikelgröße von ungefähr 15 nm bis ungefähr 150 nm, Zirkoniumoxid mit einer durchschnittlichen primären Partikelgröße von ungefähr 15 nm bis ungefähr 150 nm, Eisenoxid mit einer durchschnittlichen primären Partikelgröße von ungefähr 15 nm bis ungefähr 500 nm oder eine Mischung davon ist.
  19. Die Zusammensetzung gemäß Anspruch 14, wobei die Sonnenschutzverbindung Octylmethoxycinnamat, Octylsalicylat, Terephthalyliden-Dicamphor-Sulfonsäure, Avobenzon, Octocrylen oder eine Mischung davon ist.
  20. Verwendung eines dermatologisch verträglichen Trägerstoffs;
    einer wirksamen Menge einer Salicylatverbindung; und
    einer wirksamen Menge einer Jasmonsäureverbindung, einer Gibberellinsäureverbindung, einer Zeatinverbindung oder einer Kombination davon; zur Herstellung einer Zusammensetzung zum Fördern einer gesunden Hautentwicklung bei einem Säugetier, wobei die Zusammensetzung die Fibronektinproduktion in Säugetierfibroblasten oder den Wundverschluß in der Dermis des Säugetiers stimulieren kann.
  21. Verwendung eines dermatologisch verträglichen Trägerstoffs;
    einer wirksamen Menge einer Salicylatverbindung; und
    einer wirksamen Menge einer Jasmonsäureverbindung, einer Gibberellinsäureverbindung, einer Zeatinverbindung oder einer Kombination davon; zur Herstellung einer Zusammensetzung zur Stimulierung der Fibronektinproduktion in Säugetierfibroblasten.
  22. Verwendung eines dermatologisch verträglichen Trägerstoffs;
    einer wirksamen Menge einer Salicylatverbindung; und
    einer wirksame Menge einer Jasmonsäureverbindung, einer Gibberellinsäureverbindung, einer Zeatinverbindung oder einer Kombination davon; zur Herstellung einer Zusammensetzung zum Fördern des Wundverschlusses bei einem Säugetier, wobei die Zusammensetzung die Zellproliferation von Säugetierfibroblasten oder -keratinozyten stimulieren kann.
  23. Verwendung eines dermatologisch verträglichen Trägerstoffs;
    einer wirksamen Menge einer Salicylatverbindung; und
    einer wirksame Menge einer Jasmonsäureverbindung, einer Gibberellinsäureverbindung oder einer Kombination davon; zur Herstellung einer Zusammensetzung zum Fördern der Hautzellerneuerung bei einem Säugetier, wobei die Zusammensetzung die Rate der Hautzellemeuerung bei einem Säugetier vergrößern kann, wobei die Jasmonsäureverbindung eine Verbindung gemäß einer der Formeln VI, VII, VIII oder IX ist:
    Figure imgb0055
    Figure imgb0056
    Figure imgb0057
    Figure imgb0058
     wobei:
    R3 ist Alkyl;
    R4 ist COOR oder -(CH2) n-OX, wobei n eine ganze Zahl von 1 bis 20 ist;
    R ist H oder Alkyl;
    X ist H oder 1 bis 6 Zuckerreste; und
    Y ist Alkyl oder 1 bis 6 Zuckerreste in Formel VIII und IX.
  24. Eine Zusammensetzung zur Verwendung beim Fördern der Hautzellerneuerung, welche umfasst
    einen dermatologisch verträglichen Trägerstoff;
    eine wirksame Menge einer Salicylatverbindung; und
    eine wirksame Menge einer Jasmonsäureverbindung, einer Gibberellinsäureverbindung oder einer Kombination davon; wobei die Jasmonsäureverbindung eine Verbindung gemäß einer der Formeln VI, VII, VIII oder IX ist:
    Figure imgb0059
    Figure imgb0060
    Figure imgb0061
    Figure imgb0062
    Figure imgb0063
     wobei:
    R3 ist Alkyl;
    R4 ist COOR oder -(CH2) n-OX, wobei n eine ganze Zahl von 1 bis 20 ist;
    R ist H oder Alkyl;
    X ist H oder 1 bis 6 Zuckerreste; und
    Y ist Alkyl oder 1 bis 6 Zuckerreste in Formel VIII und IX.
  25. Die Zusammensetzung gemäß Anspruch 24, wobei die Zusammensetzung einen schnelleren Zellumsatz in Haut fördern kann, welche mit der Zusammensetzung behandelt ist, im Vergleich zu unbehandelter Haut.
  26. Die Zusammensetzung gemäß Anspruch 24, wobei die Gibberellinsäureverbindung eine Verbindung gemäß einer der Formeln III, IV, V, Va oder Vb ist:
    Figure imgb0064
    Figure imgb0065
    Figure imgb0066
    Figure imgb0067
    Figure imgb0068
  27. Die Zusammensetzung gemäß Anspruch 24, wobei die Jasmonsäureverbindung Jasmonsäure, Hydroxy-Jasmonsäure, Dihydro-Jasmonsäure oder Dihydrohydroxy-Jasmonsäure ist.
  28. Die Zusammensetzung gemäß Anspruch 24, wobei die Zusammensetzung des Weiteren eine Zeatinverbindung umfasst.
  29. Die Zusammensetzung gemäß Anspruch 28, wobei die Zeatinverbindung eine der Verbindung der Formel X ist:
    Figure imgb0069
     wobei:
    R5 ist H, 3-Hydroxymethyl-3-Methylallyl, Alkyl, -(CH2)n-CH3 oder OZ;
    Z ist H, 1 bis 6 Zuckerreste oder -(CH2)n-Furan;
    R6 ist H, 3-Hydroxymethyl-3-Methylallyl, Alkyl, -(CH2)n-CH3 oder OZ; und n ist eine ganze Zahl von 1 bis 20.
  30. Die Zusammensetzung gemäß Anspruch 28, wobei die Zeatinverbindung Zeatin ist.
  31. Die Zusammensetzung gemäß Anspruch 24, wobei die wirksame Menge an Jasmosäureverbindung oder Gibberellinsäureverbindung eine Konzentration von ungefähr 0,001 Mikromolar bis ungefähr 10 Millimolar ist.
  32. Die Zusammensetzung gemäß Anspruch 24, wobei die wirksame Menge an Jasmosäureverbindung oder Gibberellinsäureverbindung eine Konzentration von ungefähr 1 Mikromolar bis ungefähr 5 Millimolar ist.
  33. Die Zusammensetzung gemäß Anspruch 24, wobei die Zusammensetzung des Weiteren einen oder mehrere zusätzliche Inhaltsstoffe umfasst.
  34. Die Zusammensetzung gemäß Anspruch 33, wobei der zusätzliche Inhaltsstoff eine Desquamationsverbindung, eine Anti-Akne-Verbindung, eine Anti-Falten-Verbindung, eine Vitamin-B3-Verbindung, eine Vitamin-E-Verbindung, eine Retinoidverbindung, eine Hydroxysäureverbindung, eine Anti-Oxidant-Verbindung, ein Radikalfänger, ein Chelatbildner, eine Flavonoidverbindung, ein Entzündungshemmer, eine Anti-Cellulite-Mittel, ein topisches Anästhetikum, ein Bräunungsmittel, ein Hautaufhellungsmittel, ein Hautheilmittel, eine antimikrobielle Verbindung, eine antimykotische Verbindung, eine Sonnenschutzverbindung, ein teilchenförmiges Material, ein Feuchtigkeitsmittel oder ein Verdickungsmittel ist.
  35. Die Zusammensetzung gemäß Anspruch 33, wobei die Vitamin-E-Verbindung Tocopherol, Tocopherolacetat, ein Tocopherolester oder eine Mischung davon ist
  36. Die Zusammensetzung gemäß Anspruch 34, wobei die Retinoidverbindung ein Retinol, Retinal, Retinylester, Retinylpropionat, Retinsäure, Retinylpalmitat oder eine Mischung davon ist.
  37. Die Zusammensetzung gemäß Anspruch 34, wobei das teilchenförmige Material Glimmer, mit Bariumsulfat und TiO2 behandelter Glimmer, Kieselerde, Nylon, Polyethylen, Talk, Styren, Polypropylen, Ethylen/Acrylsäure Copolymer, Serizit, Aluminiumoxid, Silikonharz, Bariumsulfat, Titaniumdioxid, Eisenoxid, Wismuthoxychlorid, Kalziumkarbonat, Zelluloseacetat, Polymethyl-Methacrylat oder ein Mischung davon ist.
  38. Die Zusammensetzung gemäß Anspruch 34, wobei der Sonnenschutz ein Metalloxid ist ausgewählt aus der Gruppe bestehend aus Titaniumdioxid mit einer durchschnittlichen primären Partikelgröße von ungefähr 15 nm bis ungefähr 100 nm, Zinkoxid mit einer durchschnittlichen primären Partikelgröße von ungefähr 15 nm bis ungefähr 150 nm, Zirkoniumoxid mit einer durchschnittlichen primären Partikelgröße von ungefähr 15 nm bis ungefähr 150 nm, Eisenoxid mit einer durchschnittlichen primären Partikelgröße von ungefähr 15 nm bis ungefähr 500 nm oder eine Mischung davon ist.
  39. Die Zusammensetzung gemäß Anspruch 34, wobei die Sonnenschutzverbindung Octylmethoxycinnamat, Octylsalicylat, Terephthalyliden-Dicamphor-Sulfonsäure, Avobenzon, Octocrylen oder eine Mischung davon ist.
  40. Eine Zusammensetzung, die geeignet ist zur Verwendung in der Behandlung der Dermis, welche umfasst:
    einen dermatologisch verträglichen Trägerstoff;
    eine wirksame Menge einer Salicylatverbindung; und
    eine wirksame Menge einer Jasmonsäure, einer Gibberellinsäureverbindung, einer Zeatinverbindung oder einer Kombination davon.
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EP2522334A1 (de) 2011-05-10 2012-11-14 Cutech S.R.L. Kosmetische Zubereitungen enthaltend Diterpensäuren z.B. Gibberellinsäuren

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US7485666B2 (en) 2004-06-17 2009-02-03 Kimberly-Clark Worldwide, Inc. Vaginal health products
US7258878B2 (en) * 2004-12-20 2007-08-21 Kimberly-Clark Worldwide, Inc. Anti-microbial composition and methods of use thereof
US7558416B2 (en) * 2006-10-02 2009-07-07 Johnson & Johnson Consumer Companies, Inc. Apparatus and method for measuring photodamage to skin
FR2921255B1 (fr) * 2007-09-21 2013-12-27 Oreal Utilisation d'un derive d'acide jasmonique a titre d'agent depigmentant
WO2011010075A1 (fr) * 2009-07-24 2011-01-27 L'oreal Utilisation d'un derive d'acide jasmonique en tant qu'agent apaisant
FR2954122B1 (fr) * 2009-12-22 2012-02-10 Oreal Composition cosmetique comprenant un compose d'acide jasmonique
FR2954125B1 (fr) * 2009-12-22 2013-02-15 Oreal Composition cosmetique comprenant un compose d'acide jasmonique
US20190142719A9 (en) * 2009-12-22 2019-05-16 L'oreal Cosmetic composition comprising a jasmonic acid compound

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WO2012152615A1 (en) 2011-05-10 2012-11-15 Cutech Srl. Cosmetic compositions comprising diterpenoic acids, e.g. gibberellic acids

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AU2003299660A8 (en) 2004-07-22
WO2004058151A2 (en) 2004-07-15
EP1587505A2 (de) 2005-10-26
WO2004058151A3 (en) 2004-11-25
AU2003299660A1 (en) 2004-07-22
EP1587505A4 (de) 2007-10-31

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